M Linda, Professor And Director
Pennsylvania State University-univ Parkcity: University Park country: United States (us)
Abstract: PROJECT SUMMARY (See instructions) The purpose of the Administration, Mentoring and Dissemination Core (Admin Core) is to maintain an infrastructure that promotes the highest level of CPTM productivity, so that the CPTM can make the most progress in addressing the methodological challenges presented by substance use and HIV research. The Specific Aims ofthe Admin Core are as follows 1. To promote sustained, productive, and synergistic collaboration among CPTM investigators. This will be accomplished by maintaining a clear administrative structure and regular center-wide meetings that encourage scientific interaction. These include a thricemonthly meeting devoted to presentation and discussion of research; a monthly meeting devoted to setting and reviewing productivity goals; and yearly research retreats. 2. To promote sustained, productive, and synergistic collaboration beh/veen CPTM investigators and substance use/HIV investigators outside the CPTM, in order to keep the CPTM functioning as a bridge between substance use/HIV research and methodology. This will be accomplished primarily by extensive collaboration with substance use and HIV scientists. We will also seek the counsel of our distinguished External Advisory Committee on this and other matters. 3. To maintain a vigorous program to disseminate methodological information to substance use and HIV scientists. Our multifaceted dissemination plan includes publishing strategically in a variety of peerreivew outlets; maintaining an information-packed web site with free downloadable software; workshops and short courses; and other dissemination activities. 4. To bring new people and new ideas into the field of prevention and treatment methodology. We plan to continue to attract established scientists to the field of substance use and HIV methodology. We will continue to shape the next generation of substance use methodologists via our predoctoral and postdoctoral training activities. We will also continue and extend the reach of our pilot funds program
Keywords: Address; Advisory Committees; Alcohol or Other Drugs use; Area; base; Behavioral; Behavioral Sciences; Biometry; Businesses; career; Characteristics; Collaborations; Communication; Computer software; Counseling; Drug abuse; Drug usage; Educational workshop; Engineering; Fertilization; Fostering; Funding; Goals; Health Sciences; HIV; improved; Instruction; interest; Internet; Joints; Lead; Learning; Marketing; meetings; Mentors; Methodology; Methods; Michigan; Monitor; Morbidity - disease rate; Mortality Vital Statistics; next generation; Peer Review; Pennsylvania; post-doctoral training; pre-doctoral; Prevention; Prevention Research; Procedures; Productivity; programs; Progress Reports; Psychometrics; Publications; Publishing; Research; Research Design; Research Infrastructure; Research Methodology; Research Personnel; Resources; Scientist; Shapes; Site; Social Sciences; Statistical Methods; statistics; Structure; substance use prevention; Talents; Training; Training Activity; Universities; web site; Work
Relevance: Our research will help improve quantitative methods so that prevention and treatment research can lead to valid conclusions. Only when substance use prevention and treatment efforts are based on research of the highest methodological quality can the field make consistent progress toward eradicating drug abuse, HIV, and related morbidity and mortality
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P50DA010075-16_5913 (2011): $588600
Sponsored Links Excellgen http://Excellgen.com
CENTER FOR PREVENTION AND TREATMENT METHODOLOGY
M Linda, Professor And Director
Pennsylvania State University-univ Parkcity: University Park country: United States (us)
Grant 5P50DA010075-16 from National Institute On Drug Abuse
Abstract: This proposal requests renewed funding for the Center for Prevention and Treatment Methodology (CPTM) The overarching goal of the CPTM is to improve quantitative methods for behavioral research in the prevention and treatment of substance use, HIV, and related disorders, and to place the improved methods in the hands of prevention and treatment scientists. The CPTM Specific Alms of the CPTM are (A) To develop innovative methods for design and analysis in longitudinal research on substance use, HIV risk behaviors, and closely related areas in the behavioral sciences; (B) To develop innovative methods for research that informs building individualized interventions for prevention and treatment of substance use, HIV, and related disorders; (C) To increase the relevance of the CPTM´s work to research on HIV; and (D) To maintain and enhance the CPTM as a national resource playing a vital role in the fight against drug abuse and HIV. The proposed renewed CPTM will include two cores and four scientific projects. The scientific projects will develop innovative methodological approaches related to I. Causal inference in mediation models; II. Identifying and characterizing subgroups reflecting different profiles of risk; III. Analysis of intensive (e.g. daily) longitudinal data; and IV. Empirically building adaptive behavioral interventions. The CPTM has established itself as a national resource in several ways Our original research has been published widely in top-tier journals, both in the field of methodology and the field of substance use; we are engaged in training the next generation of methodologists, with over 30 former trainees in the work force and many more currently undergoing training; and we vigorously disseminate our methodological work in a variety of ways, including targeted publications, workshops and short courses, an information-packed web site, and free downloadable software. There is a constant and lively exchange of ideas among CPTM scientists, resulting in a high level of synergy. We are engaged in a variety of collaborative projects with drug abuse and HIV/AIDS scientists outside of the CPTM. In short, we are able to advance the field of prevention and treatment methodology very effectively by operating as a P50 center. Our research will help improve quantitative methods so that prevention and treatment research can lead to valid conclusions. Only when substance use prevention and treatment efforts are based on research of the highest methodological quality can the field makes consistent progress toward eradicating drug abuse, HIV, and related morbidity and mortality. CENTER CHARACTERISTICS
Project start date: 1997-05-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-08-046
5P50DA010075-16 (2011): $2054045
Grants awarded to M Linda
PATHOBIOLOGY OF OCCLUSIVE VASCULAR DISEASE
M Linda, Professor
University Of Texas Hlth Sci Ctr San Antcity: San Antonio country: United States (us)
Grant 5T32HL007446-30 from National Heart, Lung, And Blood Institute
Abstract: This proposal defines a multi-disciplinary postdoctoral research training program for six graduates of medicine, veterinary medicine, or the basic biomedical sciences. As has been the case for the past 25 years of this NIH-sponsored program, postdoctoral training will encompass research in areas highly relevant to cardiovascular biology/pathology and is provided by well-funded, interactive research programs within the Departments of Anesthesiology, Biochemistry, Cellular and Structural Biology, Medicine, Pathology, Pharmacology, Physiology, and Surgery at the University of Texas Health Science Center at San Antonio (UTHSCSA). Principal components of the training program include (1) active participation with graded responsibility in the research laboratory of an experienced investigator; (2) an integrated lecture series on cardiovascular (patho)biology presented by the training faculty; (3) didactic courses in the responsible conduct of research and grantsmanship/peer review (as necessary, separate courses will include the use of human subjects in biomedical research as well as biostatistics), (4) dual mentorship with a rigorous mentorship plan, and, (5) submission of an independent grant application. Trainee access to on-going departmental conferences, seminars, clinical rounds, pre- and postdoctoral graduate level courses further nhances the training experience. Research areas are encompassed within three investigative themes (1) Inflammation, Cell Injury, and Adaptation; (2) Diabetes, and (3) Cardiovascular (Patho)physiology. These overlapping themes incorporate a range of highly relevant basic biomedical science investigations that are essential to understanding the genetic, biochemical, and molecular mechanisms that contribute to cardiovascular pathobiology. Given the multi-dimensional complexities, morbidity and mortality associated with occlusive cardiovascular disease in developed countries, this postdoctoral research training program will continue to provide scientists with the requisite skills to address preventations and therapies for these prevalent disorders
Keywords: Vascular Diseases
Project start date: 1990-07-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-06-468
5T32HL007446-30 (2011): $351967
SOCIETY FOR PREVENTION RESEARCH ANNUAL MEETINGS
M Linda, Professor And Director
Society For Prevention Research, Inc.city: Fairfax country: United States (us)
Grant 5R13DA021047-09 from National Institute On Drug Abuse
Abstract: This application requests continued support of the annual scientific meetings of the Society for Prevention Research (SPR) from 05/01/06 to 04/30/11. Prevention science has the potential to reduce the prevalence of a wide range of common and costly problems including problem behaviors of childhood and adolescence, mental health problems, sexual behavior that risk HIV/AIDS, and tobacco, alcohol, and other drug use. SPR´s goals for the effective development of prevention science will contribute to public health (1) establish a broad scientific forum for the exchange of concepts, methods, and results in prevention science from increasingly diverse areas of public health; (2) create opportunities for training early career, minority, and established scientists; (3) better integrate prevention research with increasingly diverse areas of public health; and (4) disseminate prevention research-based knowledge to the scientific community, policymakers, and the lay public. The SPR meeting is the primary forum in which scientists and policy makers come into contact, early career researchers interact with senior researchers and practitioners are exposed to the scientific research behind the programs they implement. The 2005 meeting theme "Prevention Science to Public Health Promoting Well-Being in the Population" is representative of SPR´s commitment to research on effective dissemination of research-based prevention policies and programs. Each theme is supported with sub-themes such as the "Economic and Cost-Utility Analysis of Prevention Research" and "Promoting Healthy Early Childhood Development". Presenters, who are selected from peer-reviewed submissions, represent diverse scientific perspectives and share cutting-edge scientific methodology. The SPR meeting continues to be the primary vehicle for the development of prevention science. It has led to the identification of cross-cutting research and intervention methods and has fostered collaboration among basic and applied scientists working on diverse problems. These developments will be further accelerated if funds are awarded to support the Mapping Advances in Prevention Science (MAPS) task groups. These transdisciplinary groups of scientists will be organized at annual meetings and supported over two years to define and develop further research on critical topics, including integration of biological and behavioral prevention research and the translation of research into prevention practice
Keywords: ing; Adolescence; Advanced Development; Affect; AIDS/HIV problem; alcohol and other drug; Applied Research; Area; Attention; Award; base; Behavioral; Biological; biopsychosocial; career; Childhood; Collaborations; Communication; Communities; cost utility analysis; design; Development; Discipline; dissemination research; dissemination trial; Drug usage; early childhood; economic cost; Effectiveness; effectiveness trial; Ensure; Epidemiology; Etiology; evidence base; Faculty; Financial Support; Fostering; Foundations; frontier; Funding; Goals; Growth; Health behavior; high risk sexual behavior; Human; Incidence; Institutes; Intervention; intervention effect; knowledge base; Leadership; Maps; meetings; Mental Health; Methodology; Methods; Minority; National Institute of Child Health and Human Development; National Institute of Drug Abuse; National Institute of Mental Health (U.S.); National Institute on Alcohol Abuse and Alcoholism; Peer Review; Personal Satisfaction; Policies; Policy Maker; Population; Positioning Attribute; Prevalence; prevent; Prevention; Prevention Research; Preventive; Preventive Intervention; Problem behavior; Procedures; Program Development; programs; public health medicine (field); Public Policy; Recruitment Activity; Request for Applications; Research; Research Personnel; Risk; Science; Scientist; sex risk; skills; Societies; Staging; Students; symposium; Tobacco; Training; Translational Research; United States National Institutes of Health; United States Substance Abuse and Mental Health Services Administration; Work
Project start date: 2001-07-11
Project end date: 2012-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2012
5R13DA021047-09 (2010): $145000
SOCIETY FOR PREVENTION RESEARCH ANNUAL MEETINGS, 2011-2015
M Linda, Professor And Director
Society For Prevention Research, Inc.city: Fairfax country: United States (us)
Grant 1R13CA150782-01A1 from National Cancer Institute
Abstract: The transdisciplinary field of prevention science has tremendous potential to improve the nation´s health by reducing the incidence of morbidity and mortality associated with disorders such as cancer, drug addiction and alcoholism, HIV/AIDS, mental illness, cardiovascular disease, and obesity. The goal of prevention science is to develop strategies for (a) reducing unhealthful behaviors, such as use of tobacco and other drugs, alcohol abuse, risky sex, and overeating, and (b) promoting mental, emotional and physical health. The Society for Prevention Research (SPR) is an established, respected professional organization of scientists, practitioners, and policy makers devoted to advancement of the science of disease prevention and health promotion across the entire spectrum of public health areas. The cornerstone of the SPR´s efforts to advance the prevention field is its Annual Meeting. The SPR Annual Meeting, which now draws about 800 attendees per year, fills an important need for promotion of prevention science as a transdisciplinary field. These Annual Meetings vigorously promote cross-fertilization of concepts, methods, and even interventions not only across disciplines, but across content areas as well. The goal is to enhance understanding of the underlying mechanisms of health-related issues and to work towards the development of effective strategies for the promotion of health and the prevention of health problems. In this way the SPR Annual Meetings provide a means of uncovering fundamental principles of individual and population-level behavior and behavior change, and thereby are fostering a rigorous new branch of behavioral science. This application requests R13 funding to support the SPR Annual Meeting, and activities closely related to the Annual Meeting, for five years (2011-2016). The Specific Aims of the current application build on prior work of SPR committees and workgroups and on the SPR´s five-year strategic planning process. These Specific Aims are (1) to use the Annual Meeting to develop further a centrally integrated scientific forum for the exchange of new concepts, methods, and results from prevention research and related public health fields; (2) to spark, promote, and support innovation in prevention science by launching Mapping Advances in Prevention Science (MAPS) Task Forces; (3) to enhance the reach, benefits, and impact of the scientific developments emanating from the Annual Meetings and from the work of the SPR committees and MAPS Task Forces; (4) to use the Annual Meeting to provide opportunities for training, career building, and leadership development. The Society for Prevention Research Annual Meetings vigorously promote cross-fertilization of concepts, methods, and behavioral interventions not only across disciplines, but across content areas as well. The goal is to enhance understanding of the underlying mechanisms of health- related issues and to work towards the development of effective strategies for the promotion of health and the prevention of health problems. This leads to continual improvement of strategies for promoting public health and reducing morbidity and mortality
Keywords: Advisory Committees; AIDS/HIV problem; Alcohol abuse; Alcoholism; American; Americas; Antineoplastic Agents; Area; base; Behavior; behavior change; Behavior Therapy; Behavioral Sciences; behavioral/social science; Biology; Cardiovascular Diseases; career; Child; Child health care; college; Communication; Communities; Criminology; design; Development; Discipline; Disease; disorder prevention; Drug Addiction; Economics; Emotional; Ensure; evidence base; Fertilization; Fostering; Funding; Goals; Grant; Health; Health Promotion; Human Development; Hyperphagia; improved; Incidence; Individual; innovation; Institutes; Interdisciplinary Communication; Intervention; Leadership; Maps; Medicine; meetings; member; Mental disorders; Mental Health; Methodology; Methods; Morbidity - disease rate; Mortality Vital Statistics; National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute of Drug Abuse; National Institute of Mental Health (U.S.); National Institute on Alcohol Abuse and Alcoholism; Obesity; Pharmaceutical Preparations; physical conditioning; Policy Maker; Population; Prevention; Prevention Research; Preventive Intervention; Preventive Medicine; Process; Professional Organizations; programs; Psyche structure; public health medicine (field); Public Policy; Request for Applications; Research; Research Personnel; Science; Scientist; sex; Social Psychology; social science research; Social work (field); Societies; statistics; Strategic Planning; symposium; System; teacher; Time; Tobacco use; Training; Underrepresented Minority; United States National Institutes of Health; Work
Relevance: The Society for Prevention Research Annual Meetings vigorously promote cross-fertilization of concepts, methods, and behavioral interventions not only across disciplines, but across content areas as well. The goal is to enhance understanding of the underlying mechanisms of health- related issues and to work towards the development of effective strategies for the promotion of health and the prevention of health problems. This leads to continual improvement of strategies for promoting public health and reducing morbidity and mortality
Project start date: 2011-05-27
Project end date: 2012-05-26
Budget start date: 27-MAY-2011
Budget end date: 26-MAY-2012
PFA/PA: PA-10-071
1R13CA150782-01A1 (2011): $95000
STUDIES OF CHILDHOOD SOLID TUMORS
M Linda, Member
St. Jude Children´s Research Hospitalcity: Memphis country: United States (us)
Grant 5P01CA023099-33 from National Cancer Institute
Abstract: The theme of our program continues to be the integration of basic laboratory studies, animal model evaluation, and clinical trials to develop improved treatment for childhood solid tumors. The program is tightly focused on new and innovative approaches to improving cytotoxic therapy, and integrating signaling inhibitors with cytotoxic therapies. The theme of the program, developmental therapeutics for solid tumors, incorporates basic studies of how cellular stress (growth factor signaling hypoxia, DNA damage) impacts on drug sensitivity in solid tumors. Emphasis has been placed on the identification of pathways upstream and downstream of DNA damage that may be targets for new therapy, and on growth factor receptors that are involved in angiogenesis and in survival of cells treated with cytotoxic agents. We have structured the program to encompass objectives that can be accomplished within this cycle of support, and objectives that, realistically, could take longer to fulfill, but that may represent radically new approaches to curative therapy. Project 1 continues therapeutic studies of IGF-IR/Akt/mTOR inhibitors, and the role of IGF-IR signaling in childhood cancers. Project 2 extends studies that have demonstrated mTOR signaling regulates cellular response to DNA damage, and mutation frequency. Project 3 continues studies that demonstrate activation of the unfolded protein response (UPR) modulates cell sensitivity to cytotoxic agents, and will examine UPR activation in clinical tumors. Project 4 will elucidate how antiangiogenic agents may modulate the pharmacology of cytotoxic agents (ABC transporters) and provide new insights into clinically relevant ways to evaluate and monitor specific changes in tumor vascularity based on noninvasive assessments of changes in tumor blood flow/vasculature (through MRI and ultrasonography). These studies will allow building detailed pharmacokinetic and pharmacodynamic models that will assist in design of our clinical studies. Project 5 will continue novel Phase l/ll trials to test ideas emanating from the preclinical projects. We will continue to optimize therapy with topotecan and irinotecan, and initiate trials of irinotecan with rapamycin. Our trials will explore novel anti-angiogenic therapies, and investigate the single agent activity of small molecule or antibody therapy targeted to the IGF-I receptor alone or combined with rapamycin. Our intent remains to advance preclinical information to the design of clinical trials, and extend these to cooperative groups
Project start date: 1998-07-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P01CA023099-33 (2011): $2230285
ROLE OF MOLECULAR CHAPERONES IN IG BIOSYNTHESIS 11-2008
M Linda, Member
St. Jude Children´s Research Hospitalcity: Memphis country: United States (us)
Grant 5R01GM054068-15 from National Institute Of General Medical Sciences
Abstract: The differentiation of a B cell to a plasma cell represents one of the most dramatic changes in cellular architecture known. The massive increase in the secretory pathway that occurs is necessary to allow the plasma cell to become a factory dedicated to the synthesis, assembly and transport of immunoglobulin (Ig) molecules. The production of these heteromeric proteins in the endoplasmic reticulum (ER) is both aided and monitored by a group of resident ER proteins known as molecular chaperones. If the Ig protein fails to mature properly, it is identified and transferred back across the ER membrane to the cytosol for degradation by the 26S proteasome. In addition to the massive number of Ig molecules that are processed each minute in a plasma cell, the mechanisms for generating antibody diversity put further demands on ER quality control systems in B lineage cells. Thus it is not surprising that many components of this system were first identified in immune cells, and it is possible that unique elements of the ER quality control apparatus could exist in these cells. To better define the mechanisms governing the biosynthesis of Ig proteins, we continue our studies on the molecular chaperone BiP, which binds to free Ig heavy chains (HC) and prevents their transport until they assemble with light chains (LC). We hypothesize that BiP and its co-factors work together in a carefully orchestrated fashion to aid Ig assembly, monitor the success of this operation, and finally to target improperly folded or assembled Ig subunits for degradation. Furthermore, we hypothesize that distinct regions of the ER exist to accommodate the seemingly antagonistic functions of protein folding and degradation and that individual ERdj family members allow BiP to participate in these different functions. In the present proposal we wish to further delineate critical checkpoints in Ig assembly and determine the mechanisms by which they are executed. To do so, we will determine the function of three ER localized DnaJ homologues in Ig folding, assembly and turnover, define the specificity of nucleotide exchange factors in releasing BiP from unfolded proteins, and finally delineate mechanisms used to identify unassembled Ig molecules and target them for degradation. Cellular processes that aid and monitor the folding and assembly of antibodies are crucial to the development of the immune system. In addition, antibodies have been unusually good substrates for identifying components of the cellular quality control machinery and should continue to provide new insights into this complex process. Abnormalities in protein folding and ER quality control can have devastating consequences as is observed in cystic fibrosis, Alzheimer´s disease and prion diseases. Thus, a better understanding of the processes being investigated in this proposal is likely to have more global implications
Keywords: 26S proteasome; Alzheimer`s Disease; Antibodies; Antibody Diversity; Antibody Formation; Architecture; arm; B-Lymphocytes; Back; Binding (Molecular Function); Binding Sites; Biochemical; Calnexin; Cell Culture Techniques; Cell Lineage; Cell physiology; Cell surface; Cells; cellular imaging; cofactor; Complex; Cystic Fibrosis; Cytosol; Development; Disease; Elements; Endoplasmic Reticulum; Ensure; Environment; Evaluation; Family member; Funding; Genetic; Genetic Transcription; glucose-regulated protein 170; Government; Guanine Nucleotide Exchange Factors; Heavy-Chain Immunoglobulins; Homologous Gene; Immune; Immune system; Immunoglobulin Isotypes; Immunoglobulins; Individual; insight; Knockout Mice; Life; Light; Link; loss of function; lymphoblastoid cell line; Lymphocyte; Measures; Membrane; Messenger RNA; molecular chaperone GRP78; Molecular Chaperones; Monitor; Mutation; novel; Nucleotides; operation; Pathway interactions; Patients; Persons; plasma cell differentiation; Plasma Cells; Play; prevent; Prion Diseases; Process; Production; Protein Binding; protein complex; protein degradation; protein folding; protein misfolding; Proteins; public health relevance; Quality Control; Recruitment Activity; research study; response; Role; secretory protein; Specificity; Splenocyte; Substrate Specificity; success; Syndrome; System; Testing; Tissues; ubiquitin-protein ligase; Work
Relevance: Cellular processes that aid and monitor the folding and assembly of antibodies are crucial to the development of the immune system. In addition, antibodies have been unusually good substrates for identifying components of the cellular quality control machinery and should continue to provide new insights into this complex process. Abnormalities in protein folding and ER quality control can have devastating consequences as is observed in cystic fibrosis, Alzheimer´s disease and prion diseases. Thus, a better understanding of the processes being investigated in this proposal is likely to have more global implications
Project start date: 1996-04-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01GM054068-15 (2011): $386944
DIAGNOSTIC INNOVATIONS IN GLAUCOMA: STRUCTURAL ASSESSMENT
M Linda, Adjunct Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 2R01EY011008-16 from National Eye Institute
Abstract: The Diagnostic Innovations in Glaucoma Study (DIGS) Structural Assessment, funded since 1995, has led to significant improvements in our ability to detect glaucomatous optic disc damage, and a better understanding of the complex relationship between optic disc damage and corresponding visual field loss. The overall goal of this DIGS competitive renewal is to improve the detection and prediction of glaucomatous progression. Longitudinal monkey and human spectral domain optical coherence tomography (SDOCT), confocal scanning laser ophthalmoscopy (CSLO) and scanning laser polarimetry (GDx) data and images will be used to address the following 3 specific aims 1) to improve our understanding of macular, retinal nerve fiber layer, optic nerve head, pre-laminar and laminar change in normal aging and glaucoma, 2) to optimize testing protocols and imaging analysis techniques for detecting change to reduce testing required, and 3) to predict which individuals are at a high risk of progression, and which are likely to progress rapidly. In Specific Aim 1, we address several hypotheses designed to determine how best to utilize macula, optic nerve head, retinal nerve fiber layer thickness and pre-lamina and laminar measurements to differentiate between small physiologic age-related change and small-pathologic OAG related change. Measuring the velocity of these changes is emphasized. Our preliminary results suggest that computational and statistical techniques can reduce the number of CSLO images required to reproducibly detect change. Specific Aim 2 focuses on the hypothesis that these techniques when applied to SDOCT can shorten the testing required to verify change, and thereby reduce the costs of glaucoma management and clinical trials for new glaucoma therapy. To address Specific Aim 3, baseline imaging-based structural parameters and relevant clinical and demographic predictive factors will be included in multivariable Cox proportional hazards models for predicting who will develop photograph based and/or visual field based progression and who will progress rapidly. This project addresses the current National Eye Institute National Plan for Eye and Vision Research glaucoma program objectives to "develop improved diagnostic measures to detect optic nerve disease, progression, and treatment effectiveness." By identifying the most appropriate structural measures, reducing the number of tests required, and developing prediction models, this proposal will improve our ability to manage glaucoma patients with the ultimate goals of reducing both the likelihood of visual function loss and the costs of glaucoma management. Primary open angle glaucoma is a leading cause of blindness in the United States and worldwide; over 2.2 million Americans have glaucoma and that over 130,000 are legally blind from the disease. The overall goal of this competitive renewal entitled "Diagnostic Innovations in Glaucoma Study (DIGS) Structural Assessment is to improve the detection of glaucomatous progression so that the individuals that are at the highest risk of going blind from the disease are identified early and treatment initiated. Specifically, we will continue to follow a group of healthy individuals, individuals with glaucoma and those at high risk of developing the disease with the latest generation of ophthalmic diagnostic imaging instruments to 1) improve our ability to differentiate between glaucomatous changes and changes due to normal aging, 2) shorten the time to detect change and reduce costs of both glaucoma care and clinical trials of new glaucoma therapies, and 3) predict which individuals are at a high risk of progression, and which are likely to progress rapidly
Keywords: Accounting; Address; Affect; Age; age related; Aging; Agreement; American; base; blind; Blindness; Caring; Clinical; clinical care; Clinical Trials; Complex; Computing Methodologies; Cornea; cost; Cox Proportional Hazards Models; Data; Data Analyses; Data Collection; design; Detection; Diagnostic; Diagnostic Imaging; Disease; Disease Progression; Early treatment; Eye; follow-up; functional disability; Funding; Future; ganglion cell; Generations; Genetic; genetic variant; genome wide association study; Glaucoma; Goals; high risk; Human; Image; Image Analysis; improved; Individual; innovation; instrument; Lasers; Lead; legally blind; Length; macula; Measurement; Measures; Methods; Modeling; Monkeys; National Eye Institute; normal aging; Open-Angle Glaucoma; Ophthalmoscopes; Ophthalmoscopy; Optic Disk; optic nerve disorder; Optical Coherence Tomography; Pathologic; Patients; Phenotype; Physiological; polarimetry; Predictive Factor; Primary Open Angle Glaucoma; programs; Property; Protocols documentation; public health relevance; Reproducibility; research study; Resolution; Retina; retinal nerve fiber layer; Risk Factors; Scanning; Schedule; Science; sharing data; Staging; Statistical Methods; Structure; Techniques; Testing; Thick; Time; Treatment Effectiveness; United States; Vision; Vision research; Visit; Visual Fields
Project start date: 1995-04-01
Project end date: 2016-04-30
PFA/PA: PA-10-067
2R01EY011008-16 (2011): $609360
M Linda
California State University Los Angelescity: Los Angeles country: United States (us)
Grant 5R25GM049001-11 from National Institute On Minority Health And Health Disparities
Abstract: The collaboration between California State University Los Angeles (Cal State LA), Los Angeles City College, East Los Angeles College, and Pasadena City College has been very successful in developing the careers of talented community college minority students. In the period since last review, 86% of the participating students that completed the program have transferred to four-year institutions, a rate that is four to eight times better than the transfer rates of students from these community colleges. We propose continuation of this effort that is making a significant impact on the entry of minority group members into biomedical research careers. We anticipate that 80% of the participating community college students will transfer to four-year universities in science majors. This is an ambitious goal as the transfer rate from these community colleges to four-year institutions is only 9-20% overall. The program we propose for continuation is deliberately designed to 1) develop student skills in mathematics, basic sciences, and the English language as a foundation to high academic achievement in undergraduate majors in the natural sciences; 2) that students are motivated to careers the biomedical sciences through participation in solid research experiences and interaction with science faculty and other biomedical scientists, and; 3) that students are prepared for the transition from community college students to upper-division undergraduates at universities. Furthermore, we expect that at least 70% of those who transfer to Cal State LA and get further career development through participation in its MBRS-RISE or MARC U*STAR programs will continue to Ph.D. programs on graduation. The proposed program will involve many community college students beyond the 18 per year named as Bridges Scholars through many program activities such as special workshops, supplemental instruction to support success in science courses, and in seminars to motivate students about careers in biomedical research and broaden perspectives about career opportunities in the biomedical sciences. The overarching purpose of this Bridges to the Future effort is to increase the pool of well-prepared community college minority students who pursue biomedically-related majors, and significantly increase their rate of transfer to four-year institutions. This is the first step in a process that will prepare students for success in BS programs, and subsequently to pursue the PhD in the biomedical science. The relevance of the proposed project to the mission of the National Institutes of General Medical Sciences and its Minority Opportunities in Research Division is that the Biomedical Bridges to the Future program will significantly increase the participation in biomedical research careers by underrepresented minority group members who begin higher education at community colleges. The proposed project will develop considerable minority talent, broadening the diversity of intellectual perspectives available to participate in solving the nation´s biomedical research problems
Keywords: Academic achievement; Achievement; Address; American; base; Basic Science; Biology; Biomedical Research; biomedical scientist; Calculi; California; career; career development; catalyst; CCL7 gene; Chemistry; Cities; cohort; Collaborations; college; Communication; Communities; Competence; Creativeness; design; Discipline; Doctor of Philosophy; Eating; Educational aspects; Educational Curriculum; Educational workshop; English Language; Enrollment; Ethnicity aspects; experience; Faculty; Foundations; Future; Gatekeeping; Gender; Goals; Grant; Human; Human Activities; improved; Individual; Institution; Instruction; Joints; Journals; K-Series Research Career Programs; Knowledge; Learning; life history; Los Angeles; Mathematics; Measurable; Measures; meetings; member; Mentors; Minority; Minority Groups; Mission; Molecular; Names; National Institute of General Medical Sciences; Natural Sciences; Nature; Outcome; Participant; Performance; Physics; Population; Preparation; Process; Programmed Instruction; programs; Publications; Race; Reproduction; Research; Research Personnel; Science; Scientist; Series; skills; Solid; Solutions; Students; success; Talents; Time; Training; Underrepresented Minority; Universities; university student; Work; Writing
Project start date: 1992-09-30
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-07-411
5R25GM049001-11 (2011): $260992
ADOPTIVE TRANSFER OF ALLOCTL FOR IMMUNOTHERAPY OF RECURRENT GLIOMAS
M Linda, Professor
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 7R01CA125244-02 from National Cancer Institute
Abstract: The broad, long-term objectives of our research are i) to develop and optimize cellular immunotherapy approaches for the treatment of brain tumors; and ii) to gain a better understanding of the mechanisms of immune responses generated by cell-based strategies targeting central nervous system (CNS) neoplasms. Toward these goals, we have actively explored permutations of local adoptive immunotherapy for human malignant gliomas with autologous and allogeneic effector cells. We have achieved both pre-clinical and clinical success with adoptive transfer of intracavitary alloreactive cytotoxic T lymphocytes (aCTL), which are sensitized to the tumor host´s human leukocyte antigens (HLA). HLA antigens expressed on the patient´s lymphocytes are also on brain tumor cells but not on normal brain cells such as neurons and glia. Thus, the tumor-bearing host´s own HLA offers a means for targeted selective glioma cell kill by CTL sensitized to them. Aim 1 of this study is to assess the safety and feasibility of intratumoral delivery of aCTL/IL-2 in recurrent glioma patients. A Phase I clinical study will involve treatment with alloreactive CTL over ten months. The immune treatment will be administered only after the patients have failed standard radiation and chemotherapy for malignant glioma. Data relative to the clinical toxicity as observed in Aim 1 will be correlated with laboratory studies conducted in parallel. Aim 2 of the laboratory studies will determine molecular/cellular and functional characteristics of the donor aCTL infusates that may influence the clinical toxicity/response. To this end we will determine the cytotoxicity of the aCTL to relevant target, perform phenotypic analyses and determine the fold-increase in the cytotoxic T cell phenotype producing IFN-? upon exposure to relevant target cells. Aim 3 of the laboratory studies will determine the reaction of the patient´s endogenous immune cells to the treatment by assessing the ability of patient peripheral blood mononuclear cells pre- and post-treatment to secret Th1 and Th2 cytokines when stimulated with relevant targets. We will also assess local CNS host anti-tumor immune responses by analyzing cells and cytokines within the resection cavities at specific times after the aCTL have been infused. Thus, this is a truly bi-directional clinical project that is directly related to our long-term objectives stated above. The primary objective of our research is to train immune cells from healthy donors that are manipulated outside the body with various growth factors to recognize proteins on the surfaces of brain tumor cells that are not on normal brain cells. The immune cells are termed alloreactive cytotoxic T lymphocytes (aCTL) because they are sensitized to the tumor host´s human leukocyte antigens (HLA). The immune treatment will be administered only after the patients have failed standard radiation and chemotherapy. The trained immune cells will be adoptively transferred into the surgically-resected tumor beds of patients diagnosed with malignant brain tumors. Data relative to the clinical toxicity and patient response to the treatment will be correlated with laboratory studies designed to determine if the antitumor effects are due alone to the immune cells given, or whether they also activate the patient´s own immune system. This immunotherapy approach will help us gain a better understanding of the mechanisms of immune responses generated by cell-based strategies targeting tumors located in the central nervous system (CNS)
Keywords: Acute; Adoptive Immunotherapy; Adoptive Transfer; Aftercare; Aliquot; Allogenic; Anaplastic astrocytoma; Antigens; Autologous; base; Beds; Brain; brain cell; Brain Neoplasms; brain tissue; Catheters; CD3 Antigens; CD8B1 gene; cell killing; Cells; Central Nervous System Neoplasms; Characteristics; chemotherapy; Clinical; Clinical Research; cytokine; cytotoxic; Cytotoxic T-Lymphocytes; cytotoxicity; Data; Diagnosis; Dose; Effector Cell; Enrollment; Excision; Exposure to; Glioblastoma; Glioma; Goals; Growth Factor; Health Sciences; Histologic; HLA Antigens; Human; Immune; Immune response; Immune system; Immunotherapy; Implant; Infusion procedures; Injection of therapeutic agent; Interferons; Interleukin-2; Laboratory Study; Liquid substance; lymphoblast; Lymphocyte; Malignant Glioma; Malignant neoplasm of brain; Maximum Tolerated Dose; mixed gliomas; Molecular; neoplastic cell; Neuraxis; Neuroglia; Neurons; oligodendroglioma; Operative Surgical Procedures; Patients; Peripheral Blood Mononuclear Cell; Phase; phase 1 study; Phenotype; pre-clinical; prevent; Production; Proteins; Protocols documentation; public health relevance; Radiation; Reaction; Recurrence; Recurrent tumor; Regulatory T-Lymphocyte; Relative (related person); Research; Research Design; Research Subjects; Resected; response; Safety; standard of care; success; Surface; Surgically-Created Resection Cavity; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Toxic effect; Training; tumor; tumor growth
Relevance: The primary objective of our research is to train immune cells from healthy donors that are manipulated outside the body with various growth factors to recognize proteins on the surfaces of brain tumor cells that are not on normal brain cells. The immune cells are termed alloreactive cytotoxic T lymphocytes (aCTL) because they are sensitized to the tumor host´s human leukocyte antigens (HLA). The immune treatment will be administered only after the patients have failed standard radiation and chemotherapy. The trained immune cells will be adoptively transferred into the surgically-resected tumor beds of patients diagnosed with malignant brain tumors. Data relative to the clinical toxicity and patient response to the treatment will be correlated with laboratory studies designed to determine if the antitumor effects are due alone to the immune cells given, or whether they also activate the patient´s own immune system. This immunotherapy approach will help us gain a better understanding of the mechanisms of immune responses generated by cell-based strategies targeting tumors located in the central nervous system (CNS)
Project start date: 2010-07-01
Project end date: 2015-04-30
Budget start date: 26-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
7R01CA125244-02 (2011): $690480
IDENTIFICATION AND FUNCTIONAL ASSESSMENT OF AUTISM SUSCEPTIBILITY GENES
M Linda
Rutgers The St Univ Of Nj New Brunswickcity: New Brunswick country: United States (us)
Grant 5R01MH076435-05 from National Institute Of Neurological Disorders And Stroke
Abstract: The autism spectrum disorders (ASD) are a group of serious neurodevelopmental disorders characterized by deficits in communication, abnormal social interactions, and rigid or repetitive interests and behaviors. Although there is strong evidence of an important genetic contribution to the cause of ASD, the isolation of specific causative genetic defects has been difficult. This project will use existing DMA and clinical data from the AGRE and NIMH repositories to search for ASD susceptibility genes. Aim 1 will focus on the analysis of genotype data using an alternative, Bayesian approach to linkage analysis, based on the posterior probability of linkage (PPL). This method was selected as the main analysis approach as it has been demonstrated to be far more effective in extracting accurate information from gene-mapping studies of heterogeneous disorders than any of the current model-based or model-free alternatives, greatly aiding the localization of susceptibility genes. Aim 2 will focus on fine linkage and linkage disequilibrium mapping of regions identified in Aim 1. PPL linkage peaks will initially be narrowed through 1-2 cM density microsatellite mapping, followed by very high density SNP mapping. SNP genotyping will be conducted using an inexpensive, robust, flexible and scalable genotyping system based on allele-specific ligation. An extension of the PPL that incorporates Linkage Disequilibrium (LD) will be used for LD mapping of candidate genes within the linkage peaks. Aim 3 will investigate whether associated haplotypes functionally alter the candidate genes using lymphoblastoid and post-mortem samples as well as in vitro neuronal cultures and mouse knock-ins to analyze developmentally relevant cell types. Upon completion of these experiments, it is likely that ASD-associated alleles for multiple genes will be identified. Through our extensive functional analysis, we will be able to demonstrate that some of the associated haplotypes functionally alter the associated genes, making them likely candidates for risk alleles and providing genetic evidence that these genes likely act as ASD susceptibility loci. The mouse models that will be generated for some of these associated haplotypes will provide a more amenable system for future developmental, behavioral and toxicology experiments. These accomplishments will lead to important translational research so that better diagnoses, treatments and preventions can be developed for ASD
Keywords: Accounting; Affect; Alleles; Allelomorphs; Autism; autism spectrum disorder; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; base; Behavior; Behavioral; biological signal transduction; Brain; Candidate Disease Gene; Candidate Gene; Cell Communication and Signaling; Cell Signaling; cell type; Chromosome Mapping; Clinical Data; Closure by Ligation; Collection; Communication; Complex; Data; Data Linkages; Data Sources; density; Development; Diagnosis; Disease; disease/disorder; Disorder; drift mapping; Encephalon; Encephalons; experiment; experimental research; experimental study; falls; Family; family based linkage study; flexibility; Future; Gene Expression; Gene Localization; Gene Mapping; Gene Mapping, Total Human and Non-Human; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; genetic linkage analyses; genetic linkage analysis; genetic mapping; Genetics, Gene Mapping; Genetics, in situ Hybridization; Genome; genome mutation; Genotype; Haplotypes; heavy metal lead; heavy metal Pb; In Situ Hybridization; in situ Hybridization Staining Method; In Vitro; in vitro Assay; Individual; interest; Intracellular Communication and Signaling; Kanner`s Syndrome; Lead; Ligation; linkage analyses; Linkage Analysis; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Linkage Disequilibriums; Linkage Mapping; Linkages, Data; lymphoblastoid cell line; Mammals, Mice; Maps; Measures; Methods; Methods and Techniques; Methods, Other; Mice; Microsatellite Markers; Microsatellite Repeats; Microsatellites; Minor; Modeling; mouse model; Murine; Mus; Mutation; National Institute of Mental Health; National Institute of Mental Health (U.S.); Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurodevelopmental Disorder; Neurological Development Disorder; neuronal; Neurons; NIMH; novel; Pattern; Pb element; Population; predisposing gene; Predisposition; Predisposition gene; Probability; Procedures; Record Linkage Study; Regulation; repository; Research; research study; Risk; Sampling; Signal Transduction; Signal Transduction Systems; Signaling; Single Nucleotide Polymorphism Map; SNP genotyping; SNP Map; Social Interaction; Susceptibility; Susceptibility Gene; System; System, LOINC Axis 4; Techniques; Toxicology; Transcript; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; United States National Institute of Mental Health; Validation
Project start date: 2005-09-30
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
PFA/PA: RFA-MH-05-007
5R01MH076435-05 (2009): $478257
ROLE OF SMOOTH MUSCLE CELLS IN GRAFT INTIMAL HYPERPLASIA
M Linda, Professor
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 5R01HL041178-21 from National Heart, Lung, And Blood Institute
Abstract: Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited, in part due to the development of anastomotic intimal hyperplasia characterized by accumulation of smooth muscle cells (SMC) and deposition of extracellular matrix, particularly collagen type I. We have shown that 1) prosthetic graft material induces monocytic cells to oxidize LDL 2) hypercholesterolemia in rabbits increases cholesterol accumulation in graft compared to native aorta, 3) lipid oxidation products accumulate in grafts compared to adjacent aorta, and 4) oxidized LDL (oxLDL) stimulates platelet-derived growth factor (PDGF) and collagen production by graft SMC but has less effect on aortic SMC. In preliminary studies we have shown that reactive oxygen species (ROS) stimulate a very rapid increase in SMC collagen synthesis without an increase in mRNA. Also ROS increase intracellular concentration of free calcium ([Ca2+]i) and activate protein kinase C-delta (PKCdelta). PKC8 can phosphorylate proteins in the translation initiation complex. Based on our preliminary studies, we propose as an overall hypothesis that lipid oxidation products formed within synthetic vascular grafts create an oxidative stress that stimulates collagen production by SMC though several mechanisms including, a rise in [Ca2+]i and increased translation due to PKCdelta-mediated phosphorylation of initiation factors. Elevated collagen contributes to the development of intimal hyperplasia. We will test our hypothesis by investigating the mechanisms of ROS-induced collagen production and the elevated sensitivity of graft SMC. We will assess levels of endogenous antioxidants in aortic and graft SMC. We will explore the role of elevated [Ca2+]i in increased collagen production, and the mechanism of ROS mediated increase in [Ca2+]i, particularly the role of TRPC6 calcium channels. We will investigate the role of ROS-activated PKCdelta in the increased collagen synthesis. Finally, we will assess the mechanism of translational regulation of collagen production, specifically the role of phosphorylation of initiation factors, and the existence of cellular factors that influence transcript-specific regulation of procollagen mRNA translation. The proposed studies will determine the role of oxLDL and ROS in the increased collagen production by SMC from synthetic vascular grafts compared to SMC from native aorta. Studies will also address the efficacy of antioxidants to control the collagen production. This will lead to a better understanding of the role of lipids in graft healing, and ultimately, to methods limiting collagen synthesis and the development of intimal hyperplasia of prosthetic grafts, thereby prolonging patency of small-diameter vascular grafts
Keywords: Abbreviations; Active Oxygen; Address; Agonist; Angioplasty; anti-oxidant; Antioxidants; Aorta; base; beta-Lipoproteins; Blood Coagulation Factor IV; Blood Vessels; Ca++ element; Calcium; calcium antagonist; Calcium Antagonists, Exogenous; Calcium Blockaders, Exogenous; Calcium Channel; Calcium Channel Antagonist Receptor; Calcium Channel Blockers; Calcium Channel Blocking Drugs; Calcium Inhibitors, Exogenous; Caliber; Cardiovascular Diseases; cardiovascular disorder; Cell-Extracellular Matrix; Cells; Cholest-5-en-3-ol (3beta)-; Cholesterol; Chronic; Coagulation Factor IV; Collagen; Collagen Type I; Complex; Data; Deposit; Deposition; Development; Diameter; Eating; ECM; Endothelial Cells; Extracellular Matrix; Factor IV; Food Intake; gene product; Genetic Translation; Goals; graft failure; graft healing; Graft Material; heavy metal lead; heavy metal Pb; Hypercholesteremia; hypercholesterolemia; Hyperlipemia; Hyperlipidemia; Hyperplasia; Hyperplastic; implantation; improved; inhibitor; inhibitor/antagonist; Initiation Factors; intraluminal angioplasty; Ion Channels, Calcium; LDL; Lead; Leiomyocyte; Lipids; Lipoproteins, LDL; Low-Density Lipoproteins; macrophage; Mammals, Rabbits; Mediating; membrane activity; Messenger RNA; Methods; mRNA; mRNA Translation; Myocytes, Smooth Muscle; Oral; Oryctolagus cuniculus; ox-LDL; oxidation; Oxidative Stress; oxidized LDL; oxidized low density lipoprotein; Oxis; OxLDL; Oxygen Radicals; Patients; Pb element; PDGF; Peptide Initiation Factors; Performance; Phosphorylation; Platelet-Derived Growth Factor; Pro-Oxidants; Procollagen; Production; Prosthesis; Prosthetic device; Prosthetics; protein kinase C-delta; Protein Phosphorylation; Proteins; Rabbit, Domestic; Rabbits; Reactive Oxygen Species; Receptors, Calcium Channel Blocker; reconstructive surgery; Reconstructive Surgical Procedures; Regulation; Research; response; restenosis; RNA, Messenger; Role; Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; social role; Surface; Testing; Therapeutic Agents; trans acting factor (genetic); Trans-Acting Factors; Trans-Activators; Transactivators; Transcript; Translation Initiation; Translation Initiation Factor; Translational Initiation Factor; Translational Regulation; Translations; Transplanted tissue; Type 1 Collagen; vascular; Vascular Graft; VDCC; Voltage-Dependent Calcium Channels
Project start date: 1989-07-01
Project end date: 2011-11-30
Budget start date: 1-DEC-2008
Budget end date: 30-NOV-2011
5R01HL041178-21 (2009): $362679
Sponsored Links Excellgen http://Excellgen.com
EFFECT OF LIPIDS ON VASCULAR GRAFT HEALING
M Linda, Professor
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 2R01HL064357-09A2 from National Heart, Lung, And Blood Institute
Abstract: Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited by their thrombogenicity and the development of intimal hyperplasia. Oxidized LDL and lysophosphatidylcholine (lysoPC), a product of LDL oxidation, accumulate in grafts and alter cell function. The long-term goal of our research is to improve the patency of vascular grafts by promoting endothelial cell (EC) healing of graft surfaces. LysoPC inhibits EC migration in vitro, and hypercholesterolemia reduces EC migration into injured arteries and onto grafts. Old and lysoPC increase cellular production of reactive oxygen species, increase cell membrane fluidity, and open ion channels. These effects can inhibit EC migration. Specifically, lysoPC activates a canonical transient receptor potential (TRPC) ion channel, TRPC6, which opens TRPC5 through a unique TRPC activation cascade, leading to a prolonged rise in intracellular free calcium ion concentration ([Ca2+]i). Increased [Ca2+]i inhibits EC migration by activation of calpains that breakdown cytoskeletal proteins essential for migration. This proposal addresses the hypothesis that lipid oxidation products formed within synthetic vascular grafts inhibit their EC migration, in part through activation of TRPC6 and TRPC5 channels, and thereby limit endothelialization of grafts in vivo. The goals of this project are to identify mechanisms by which lipid oxidation products activate TRPC6 and TRPC5 channels and identify ways to counteract this. To accomplish these goals, the mechanism by which lipid oxidation products activate TRPC6, specifically the roles of Src kinases and phospholipase C-31, will be explored. In addition, and the mechanism by which TRPC6 activates TRPC5 will be studied, focusing on the role of intracellular calcium and myosin light chain kinase. The role of reactive oxygen species and changes in membrane fluidity in these actions will also be explored. Finally, the ability of an apoA-I mimetic or HDL, which we have shown to block the TRPC6-TRPC5 activation cascade in vitro, to improve EC migration in areas of arterial injury in mice and onto prosthetic grafts implanted in normal and hypercholesterolemic rabbits will be assessed. The proposed studies will investigate a mechanism by which lipid oxidation products limit EC healing of vascular injuries and synthetic vascular grafts. Studies will also address the ability of HDL to promote EC healing. These studies will lead to a better understanding of the role of lipids in the pathophysiology of graft failure, and provide impetus for development of TRPC6 channel inhibitors or agents that interrupt the TRPC6- TRPC5 activation cascade. These mechanism-based therapies will promote endothelial healing of angioplasty sites and prosthetic grafts to prolong their patency for the benefit of all people undergoing cardiovascular interventions. The long-term goal of our research is improve the healing of bypass grafts or arteries after balloon angioplasty and stenting. We will investigate how oxidized lipids block the movement of endothelial cells (cells that normally line blood vessels) into an area of injury or onto a bypass graft. Specifically, we will study the role of certain ion channels (TRPC channels) that when eliminated abolish the inhibitory effect of high cholesterol in a mouse model. The results of these studies will provide direction in the development of treatments to promote endothelial cell healing after vascular interventions. For example, a TRPC6 inhibitor could increase endothelial cell migration and promote healing of arterial injuries and vascular grafts for the benefit all patients who require cardiovascular interventions
Keywords: Address; Anastomosis - action; Angioplasty; Animals; Aorta; Apolipoprotein A-I; Area; Arterial Injury; Arteries; atherogenesis; Balloon Angioplasty; base; Blood Vessels; Bypass; Calcium; Calcium Channel; Calcium ion; Calpain; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell membrane; cell motility; Cell physiology; Cell surface; Cells; Cholesterol; Cholesterol Esters; Complex; Cytoskeletal Proteins; Data; Deposition; design; Development; Diet; Disease; Endothelial Cells; Extracellular Matrix; Focal Adhesions; Functional disorder; Goals; graft failure; graft function; graft healing; Growth; Healed; healing; High Density Lipoproteins; Human; hypercholesterolemia; Hyperlipidemia; Hyperplasia; Implant; improved; improved functioning; In Vitro; in vivo; Infiltration; Inflammatory; Inflammatory Response; inhibitor/antagonist; injured; Injury; Intervention; Ion Channel; Lead; Lipids; Lipoproteins; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Lysophosphatidylcholines; macrophage; Membrane Fluidity; migration; mimetics; Modeling; mouse model; Movement; Mus; Myosin Light Chain Kinase; Nicotinic Acids; novel strategies; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; oxidation; oxidized lipid; oxidized low density lipoprotein; Pathway interactions; Patients; Phospholipase; Phospholipase C; Phosphotransferases; Play; prevent; Production; Property; Prosthesis; protein kinase C-delta; Proteins; public health relevance; Reactive Oxygen Species; receptor; Reconstructive Surgical Procedures; Research; Role; Site; src-Family Kinases; Structural Protein; Surface; Testing; therapy development; Time; Vascular Graft
Relevance: The long-term goal of our research is improve the healing of bypass grafts or arteries after bal- loon angioplasty and stenting. We will investigate how oxidized lipids block the movement of endothelial cells (cells that normally line blood vessels) into an area of injury or onto a bypass graft. Specifically, we will study the role of certain ion channels (TRPC channels) that when eliminated abolish the inhibitory effect of high cholesterol in a mouse model. The results of these studies will provide direction in the development of treatments to promote endothelial cell heal- ing after vascular interventions. For example, a TRPC6 inhibitor could increase endothelial cell migration and promote healing of arterial injuries and vascular grafts for the benefit all patients who require cardiovascular interventions
Project start date: 1999-12-01
Project end date: 2015-01-31
Budget start date: 15-MAR-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-067
2R01HL064357-09A2 (2011): $456174
LIPID MODULATION OF POTASSIUM CHANNELS
M Linda
University Of Richmondcity: Richmond country: United States (us)
Grant 1R15GM096142-01 from National Institute Of General Medical Sciences
Abstract: Our project focuses on modulation of potassium ion channels by membrane-derived polyunsaturated fatty acids (PUFAs) such as arachidonic acid. PUFAs are important dietary lipids and are released from the membrane as lipid signals following certain forms of cellular communication. Voltage-gated Kv4 channels are important in rhythmic firing, learning, and excitability of the heart. They are implicated in disease states such as epilepsy, pain, memory disorders, and cardiac arrhythmia. TREK and TRAAK channels are PUFA- and mechanosensitive members of the K2P family of potassium channels. K2P channels are important in maintaining the resting excitability of cells and opposing increases in excitability. They are implicated in sensing membrane stretch and osmotic changes and may provide protection against ischemic damage. PUFAs modify the activity of both of these types of potassium channels and our research goal is to determine how this occurs at the molecular level so that we can understand how lipid signals impact neural activity. We will study the ion channels by electrophysiology and will use structural models, computational work, and molecular modifications of the channels to reach our research goal. We will determine how PUFAs interact with different gating states or shape changes of the Kv4 channel. To test this at the molecular level, we will make structural changes that alter how the channels function and will measure the impact on PUFA effects on the channel. We will examine the relationship between changes in membrane stretch and the effects of PUFAs. Finally, we will use a structural model of the channel which we built to identify possible lipid binding pockets on the channel. For K2P channels, how PUFAs open the channels will be tested by strategic use of a novel K2P channel cloned from a marine sponge which is distantly related to the mammalian channels. Our preliminary data suggest that the sponge channel is sensitive to PUFAs but not to mechanical forces in the membrane; this is in contrast to the TREK and TRAAK mammalian K2P channels which simultaneously possess sensitivity to PUFAs and membrane stretch. Molecular and physiological comparisons of the sponge and mammalian channels will be used to identify the structural regions that are required and sufficient for PUFA sensitivity. Because K2P channels are regulated by another lipid signal, PIP2, we will assess possible physiological interactions of the two lipids on the K2P channels. The principal investigator is an experienced ion channel biologist who has successfully mentored 24 undergraduate research students in 6 years at the University of Richmond. Her lab provides an excellent environment for undergraduates to pursue their interests in biomedical research. In addition to the research goal, a second goal of this project is to provide undergraduate students with valuable opportunities to participate actively in the scientific process by engagement in this research program. Our project addresses the molecular basis for the regulation of certain potassium ion channels by PUFAs, omega-3 fatty acids which are important structural components of cell membranes and important dietary lipids. This research has important health implications for how lipid signals impact the proper rhythmic firing of heart muscle and some regions of the brain, memory disorders, pain, ischemic damage during stroke and heart attack, and the physiological and pathological consequences of membrane stretch and changes in tissue salt concentration. A better understanding of how certain lipid signaling molecules alter cellular excitability is an important goal in biomedical research
Keywords: Address; Affect; Apoplexy; Arachidonic Acids; Arrhythmia; base; biological signal transduction; Biomedical Research; Body Tissues; brain attack; Brain region; Cardiac; Cardiac Arrhythmia; cardiac infarct; Cardiac infarction; cardiac muscle; Cardiac Myocytes; Cardiocyte; cardiomyocyte; Cell Communication and Signaling; Cell membrane; Cell Signaling; Cell Volumes; Cells; Cerebral Stroke; cerebral vascular accident; Cerebrovascular accident; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Communication; coronary attack; coronary infarct; coronary infarction; Cyclicity; Cytoplasmic Membrane; Data; Dietary Fats; dietary lipid; Disease; disease/disorder; Disorder; Docking; drug/agent; Drugs; Electrophysiology; Electrophysiology (science); Environment; epilepsia; Epilepsy; Epileptic Seizures; Epileptics; epileptiform; epileptogenic; experience; Family; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Polyunsaturated; gene product; Genetic Alteration; Genetic Change; Genetic defect; Genetics-Mutagenesis; genome mutation; Goals; Health; Heart; Heart Arrhythmias; heart attack; heart infarct; heart infarction; heart muscle; Heart myocyte; Homology Modeling; Hydrophobic Surfaces; improved; interest; Intracellular Communication and Signaling; Ion Channel; Ion Channels, Potassium; Ionic Channels; K channel; KCND2 channel; Kv4 channel; Kv4.2 channel; Lateral; Learning; Ligands; Lipid Binding; Lipids; Marines; Measures; Mechanics; Medication; member; Membrane; Membrane Channels; Membrane Potentials; membrane structure; Memory; Memory Disorders; Mentors; Modification; Molecular; Molecular Biology, Mutagenesis; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle, Cardiac; Muscle, Heart; Mutagenesis; Mutagenesis, Site-Directed; mutant; Mutation; Myocardial Infarct; Myocardial Infarction; Myocardium; Myocytes, Cardiac; n-3 Fatty Acids; Nerve Cells; Nerve Unit; Nervous; neural; Neural Cell; Neurocyte; neuronal; neuronal excitability; Neurons; Neurophysiology / Electrophysiology; novel; omega-3; Omega-3 Fatty Acids; Omega-3 Polyunsaturated Fatty Acid; Omega-3 PUFA; Pain; Painful; Periodicity; Pharmaceutic Preparations; Pharmaceutical Preparations; Phosphatidylinositol 4, 5-Biphosphate; Phosphatidylinositol 4, 5-Diphosphate; Phosphatidylinositol-4, 5-Bisphosphate; Physiologic; Physiological; PIP2; Plasma Membrane; plasmalemma; polyunsaturated fatty acid; Polyunsaturated Fatty Acids; Porifera; Potassium Channel; pressure; Pressure; Pressure- physical agent; prevent; preventing; Principal Investigator; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Proteins; PtdInsP2; PtIns 4, 5-P2; public health relevance; Regulation; relating to nervous system; Research; Rest; Resting Potentials; Retention Disorders, Cognitive; Rhythmicity; Role; salt; Seizure Disorder; Shapes; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Site; Site-Directed Mutagenesis; Site-Specific Mutagenesis; social role; Sodium Chloride; Sodium chloride (NaCl); Solutions; Sponges; Sponges (Zoology); Stimulus; Stretching; Stroke; stroke; Structural Models; Students; Targeted DNA Modification; Targeted Modification; Testing; Tissues; TRAAK channel; Transmembrane Potentials; Universities; V (voltage); Vascular Accident, Brain; voltage; Work
Relevance: Our project addresses the molecular basis for the regulation of certain potassium ion channels by PUFAs, omega-3 fatty acids which are important structural components of cell membranes and important dietary lipids. This research has important health implications for how lipid signals impact the proper rhythmic firing of heart muscle and some regions of the brain, memory disorders, pain, ischemic damage during stroke and heart attack, and the physiological and pathological consequences of membrane stretch and changes in tissue salt concentration. A better understanding of how certain lipid signaling molecules alter cellular excitability is an important goal in biomedical research
Project start date: 2011-03-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 28-FEB-2014
PFA/PA: PA-10-070
1R15GM096142-01 (2011): $278682
GENETIC, BEHAVIORAL, AND PSYCHOSOCIAL FACTORS LINKING CHILD MALTREATMENT TO HEALT
M Linda
John Jay College Of Criminal Justicecity: New York country: United States (us)
Grant 1R01HD072581-01 from Office Of The Director, National Institutes Of Health
Abstract: One childhood stressor - child maltreatment - represents a serious public health concern. In 2007, over 3 million children were referred to child protection service agencies for suspected maltreatment in the United States and about 794,000 were determined by state and local child protective service agencies to be victims of maltreatment (DHHS, 2009). Increasing evidence shows that childhood physical and sexual abuse and (more recently) neglect have extensive short- and long-term consequences across multiple domains, including psychiatric, social, emotional, behavioral, academic, and physical functioning, and developmental time points. The associated costs to society have been estimated at billions of dollars annually. At the same time, the negative sequelae of childhood victimization are not inevitable. While explanations for these different outcomes remain unknown, research has begun to examine factors that might buffer or protect maltreated children from negative consequences. Recent research has reported significant interactions between childhood maltreatment and genetic variation in predicting psychological and behavioral outcomes, including violence and antisocial behavior, depression, anxiety, suicidality, alcoholism, and substance use. The overarching goal of the proposed research is to test three competing models of the processes whereby child abuse and neglect lead to mental and physical health consequences in adulthood. The research proposed here represents a continuation of a longitudinal study begun in 1986 with a large group of documented cases of childhood physical and sexual abuse and neglect (ages 0-11) and a comparison group of non-abused and non-neglected children who were matched on the basis of age, sex, race/ethnicity, and approximate family social class and followed up into adulthood with four interviews. We propose to use blood and saliva samples that have already been collected as part of previous waves of the study. Our goal is to identify, genotype, and analyze genetic variants and to determine whether they play a role in the long-term physical and mental health consequences of child abuse and neglect. The proposed research will lead to increased understanding of the multiple pathways through which stressful childhood experiences (such as child neglect and abuse) lead to the development of different mental and physical health outcomes and is in keeping with President Obama´s emphasis on health care education and the prevention of negative health outcomes. Determining the interplay between genetic and environmental factors that increase risk for negative physical and mental health outcomes or promote resiliency among abused and neglected children has implications for treatment and prevention efforts for these children. By determining whether a particular environment (such as an abusive or neglectful home) is particularly problematic for children with certain genes, we hope that the proposed research will provide directions for focused interventions. Child maltreatment, one major source of childhood stress, is a serious public health problem, with about 800,000 substantiated cases of childhood victimization each year. Recent research has reported significant interactions between child maltreatment and genetic variations in predicting psychological and behavioral outcomes. The overarching goal of the proposed research is to test three models that have been proposed to understand the linkages between childhood maltreatment and long-term physical and mental health consequences and, ultimately, may lead to the development of appropriate intervention strategies
Keywords: abuse neglect; Acute; Adolescent; ADRA2A gene; Adult; Affect; Age; Alcohol abuse; Alcohol or Other Drugs use; Alcoholism; allostatic load; Anthropology; anti social; Anxiety; base; Behavior; Behavioral; Behavioral Genetics; Biological; Blood; Brain-Derived Neurotrophic Factor; Buffers; Candidate Disease Gene; Child; Child Abuse; Child Abuse and Neglect; child neglect; child protective service; Childhood; Chronic; Cognitive; cohort; Collaborations; comparison group; cost; criminal behavior; Criminology; Data; Decision Making; design; Development; Discipline; Disease; Drug abuse; Elderly; Emotional; Environment; Environmental Risk Factor; Enzymes; Ethnicity aspects; Exhibits; experience; Family; Family Study; follow-up; Funding; Genes; Genetic; genetic analysis; Genetic Markers; genetic variant; Genotype; Goals; Health; Health behavior; Health Psychology; Healthcare; high risk; Home environment; Impulsivity; innovation; interest; Intervention; Interview; Lead; Life; Life Style; Link; Literature; Longitudinal Studies; maltreated children; maltreatment; Measures; Medicine; Mental Depression; Mental Health; Modeling; Monoamine Oxidase A; neglect; Neurotransmitters; Outcome; Pathway interactions; Pediatrics; Performance; Persons; physical abuse; physical conditioning; Physical Function; Physiological Processes; Play; Prevention; Prevention education; Preventive Intervention; Process; prospective; Psychiatry; psychologic; Psychologist; psychosocial; Psychosocial Factor; Psychosocial Stress; public health medicine (field); Race; Reporting; Research; Research Personnel; response; Risk; Role; Saliva; Sampling; Self-control as a personality trait; sex; Sexual abuse; social; Social Class; Societies; Source; statistics; Stress; stressor; Suicide; Testing; therapy design; Time; United States; Variation (Genetics); Victimization; Violence
Relevance: Child maltreatment, one major source of childhood stress, is a serious public health problem, with about 800,000 substantiated cases of childhood victimization each year. Recent research has reported significant interactions between child maltreatment and genetic variations in predicting psychological and behavioral outcomes. The overarching goal of the proposed research is to test three models that have been proposed to understand the linkages between childhood maltreatment and long-term physical and mental health consequences and, ultimately, may lead to the development of appropriate intervention strategies
Project start date: 2011-09-30
Project end date: 2014-08-31
Budget start date: 30-SEP-2011
Budget end date: 31-AUG-2012
1R01HD072581-01 (2011): $512756
ELUCIDATING THE ROLE OF MIRNA DYSREGULATION IN SCHIZOPHRENIA AND BIPOLAR DISORDER
M Linda
Rutgers The St Univ Of Nj New Brunswickcity: New Brunswick country: United States (us)
Grant 5R01MH080429-05 from National Institute Of Mental Health
Abstract: microRNAs are powerful regulatory molecules that are abundantly expressed in the developing and adult mammalian brain. Many primate-specific microRNAs are now known, making this class of genes attractive candidates for involvement in brain disorders such as schizophrenia and bipolar affective disorder. Little is know about the pattern of expression of microRNAs in the brains of normally developing humans or individuals with these disorders. Multiple possible mechanisms exist through which microRNAs could play a role in disease. This project will utilize a variety of experimental approaches to increase our knowledge of the normal expression and function of microRNAs in the developing and adult brain, and investigate the possible role of microRNA in the susceptibility to schizophrenia and bipolar disorder. First, we will quantify microRNA expression in normal human brain tissue from several developmental stages as well as from a matched set of samples from individuals with schizophrenia, bipolar disorder, and psychiatrically normal controls (35 individuals from each group) to provide baseline knowledge about microRNA expression in the normally developing human brain and search for evidence that some microRNAs are improperly expressed in schizophrenia and/or bipolar disorder. Second, we will search for population variability in the sequences of microRNAs and their targets in mRNAs of interest in schizophrenia and bipolar disorder, as these may be functional variants that increase disease risk. Third, we will test these candidate variants, as well as tagSNPs from a limited number of microRNA clusters, for association to schizophrenia and bipolar disorder using trios from the NIMH Genetic Initiative collection. Fourth, we will develop a list of 12 microRNAs of greatest interest based on evidence of involvement in the biology of schizophrenia and bipolar disorder from the prior three steps, and use a cell culture/transfection system to manipulate microRNA expression and validate mRNA targets. Fifth, we will characterize the temporal and spatial expression of the 12 microRNAs of interest and select targets. Sixth, we will use a cell culture/transfection system to systematically characterize the cell biological consequences of alteration in microRNA expression on neuronal development and functioning. A better understanding of microRNA function in the normal and pathological state could provide novel insights into new therapeutic approaches for schizophrenia and bipolar disorder
Keywords: Adult; Affect; base; Biological; Biological Assay; Biology; Bipolar Disorder; Brain; Brain Diseases; brain tissue; Candidate Disease Gene; Cell Culture System; Cell Culture Techniques; Cell Cycle; Cell Death; Cell physiology; Cell Proliferation; Cell Survival; cell type; Cells; Code; Collection; cost effective; Data; Detection; Development; Disease; Disease susceptibility; disorder risk; DNA Resequencing; Evaluation; Gene Expression; Gene Targeting; Genes; Genetic; genetic association; Genomics; Genotype; Grant; Human; In Situ; Individual; insight; interest; Knowledge; Length; Ligase; Luciferases; Mediating; Mental disorders; Messenger RNA; Methods; MicroRNAs; Molecular; Molecular Profiling; Mus; National Institute of Mental Health (U.S.); neuron development; Neurons; Neurotransmitters; novel; novel therapeutic intervention; Pathogenesis; Pathology; Pattern; Play; Population; precursor cell; Predisposition; pressure; Primates; Process; programs; Proteins; Reaction; Regulation; Reporter; Reproducibility; Research Personnel; research study; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Sampling; Schizophrenia; Site; small molecule; Staging; Stretching; synaptogenesis; System; Testing; Tissues; Transfection; Validation; Variant
Project start date: 2007-04-25
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-MH-07-040
5R01MH080429-05 (2011): $629501
STRUCTURE AND DYNAMICS OF BACTERIAL MEMBRANE PROTEIN - RECEPTOR INTERACTIONS
M Linda, Assistant Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5R01GM087828-03 from National Institute Of General Medical Sciences
Abstract: Many obligate bacterial membrane proteins hijack human cellular pathways by mimicking or manipulating host machinery. The goal of this research is to investigate the structure and dynamics of bacterial outer membrane proteins and their interactions with host receptors. Specifically, research is focused on the outer membrane opacity-associated proteins (Opa) from Neisseria gonorrhoeae and Neisseria meningitides, which induce engulfment of the bacterium in non-phagocytic cells by binding to host receptors. Opa proteins bind to various host receptors and are classified into two families based on host receptor selectivity. The larger class, OpaCEA, bind to carcinoembryonic antigen-like cellular adhesion molecules (CEACAMs), and the smaller class, OpaHS, bind to two different receptors; the heparansulfate proteoglycan receptors (HSPGs) directly and indirectly to integrin receptors via a heparin- mediated interaction with fibronectin or vibironectin. Opa proteins are integral outer membrane proteins and predicted to have an eight-stranded 2-barrel fold. Two of the extracellular loops (HV1 and HV2) have the most sequence variation between Opa proteins and determine the host receptors specificity. Not only do the HV loops discriminate between HSPG and CEACAM receptors, but OpaCEA proteins can be further divided into subgroups based on the selective binding to four of the seven CEACAM receptors. Using nuclear magnetic resonance, electron paramagnetic resonance, isothermal titration calorimetry, and mutagenesis, the molecular determinants of these interactions will be determined. The results will provide insight into the pathogenesis of Neisseria gonorrhoeae and Neisseria meningitides and, therefore, the potential for the rational design of novel antibiotics. In addition, the reconstituted Opa proteins may be useful for vaccine development. However, the most novel application of this research lies in the ability of Opa proteins to target host receptors specifically via three different mechanisms to induce endocytosis in non-phagocytic cells. This ability may be useful for liposome pharmaceutical carriers. The potential ability of liposome encapsulated therapeutics (e.g. enzymes, inhibitors, and peptides) to enter the cytoplasm of living cells and possibly tissue selectively is of crucial importance to the treatment of many diseases. Understanding the molecular determinants of the three Opa-mediated entry mechanisms may facilitate the development of liposome delivery mechanisms. This research aims to determine how bacteria interact with human cells. By gaining an understanding of these molecular interactions, insights into the rational design of novel antibiotics, vaccine development, and targeting of liposome pharmaceutical carriers will be obtained
Keywords: Adhesion Molecule; Affinity; alpha 2-Surface Binding Glycoprotein; Antibiotic Agents; Antibiotic Drugs; Antibiotics; backbone; Bacteria; Bacterial Outer Membrane Proteins; base; Binding; Binding (Molecular Function); Body Tissues; Caliber; Calorimetry; carcinoembryonal antigen; Carcinoembryonic Antigen; Carcinoembryonic Antigen CGM2; Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5; CD66a antigen; CD66e Antigen; CDR; CEACAM1; Cell Adhesion; Cell Adhesion Molecules; cell adhesion protein; Cell Line; Cell Lines, Strains; CellLine; Cells; Cellular Adhesion; Chemicals; Cold-Insoluble Globulins; Complementarity Determining Regions; Complimentarity Determining Region; cultured cell line; Cytoplasm; design; designing; Development; Diameter; Disease; disease/disorder; Disorder; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; E coli; Electron Paramagnetic Resonance; electron paramagnetic resonance spectroscopy; Electron Spin Resonance; Electron Spin Resonance Spectroscopy; Encapsulated; Endocytosis; Environment; Enzyme Antagonist; Enzyme Inhibitor; Enzyme Inhibitor Agent; Enzyme Inhibitor Drugs; Enzyme Inhibitors; EPR spectroscopy; Escherichia coli; expectation; experiment; experimental research; experimental study; extracellular; Extracellular Matrix, Integrins; Family; Fibronectin 1; Fibronectins; FN1; FNZ; Foundations; gene product; Genetics-Mutagenesis; Goals; Gonococcus; Health; Height; HeLa; Hela Cells; Heparin; Heparinic Acid; Human; Human, General; Hypervariable Loop; Hypervariable Regions; Immunoglobulin Hypervariable Region; insight; Integrins; interest; Large External Transformation-Sensitive Protein; LETS Proteins; Life; lipid bilayer membrane; Lipid Bilayers; Lipids; Liposomal; Liposomes; Man (Taxonomy); Man, Modern; Maps; Measures; Meconium Antigen 100; Mediating; Membrane; Membrane Proteins; membrane structure; Membrane-Associated Proteins; Meningitis; Methods; Methods and Techniques; Methods, Other; Micelles; Miscellaneous Antibiotic; Molecular; Molecular Biology, Mutagenesis; Molecular Interaction; Mutagenesis; mutant; N Domain; N. gonorrhoeae; N.gonorrhoeae; Neisseria; Neisseria gonorrhoeae; new therapeutics; next generation therapeutics; novel; novel therapeutics; Nuclear Magnetic Resonance; OMP Proteins; Opsonic alpha(2)SB Glycoprotein; Opsonic Glycoprotein; Paramagnetic Resonance; Pathogenesis; pathway; Pathway interactions; Peptides; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Protein Binding; protein structure; protein structure function; Proteins; Proteoglycan; receptor; Receptor Protein; reconstitute; reconstitution; Relaxation; Reporting; Research; research study; Site; Solutions; Specificity; Spectroscopy; Spectroscopy, ESR; Spectrum Analyses; Spectrum Analysis; Spin Labels; Spinal Column; Spine; Structure; SUBGP; Subgroup; Surface Proteins; System; System, LOINC Axis 4; Techniques; Testing; Therapeutic; Thermodynamic; Thermodynamics; Tissues; Titrations; vaccine development; Variant; Variation; Vertebral column; Work
Relevance: This research aims to determine how bacteria interact with human cells. By gaining an understanding of these molecular interactions, insights into the rational design of novel antibiotics, vaccine development, and targeting of liposome pharmaceutical carriers will be obtained
Project start date: 2009-04-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-253
5R01GM087828-03 (2011): $275414
CLINICIANS´ CONCEPTS OF RACIAL/ETHNIC DIFFERENCES IN THE MANAGEMENT OF CHRONIC IL
M Linda, Associate Professor
Michigan State Universitycity: East Lansing country: United States (us)
Grant 5R01HG004710-03 from National Human Genome Research Institute
Abstract: Genetic knowledge is becoming increasingly central to the way human health and disease are understood and addressed. In order to advance the translation of medical knowledge into effective practice, it is important to know how genetic knowledge is presently understood by clinicians and patients, and applied in their routine medical encounters. Genetic information is already being translated from the ed world of laboratory research to the practical context of clinical practice and everyday life. At the same time, there is great interest in understanding and alleviating the unequal burden of disease affecting certain racial/ethnic populations in the U.S. Research has shown that health disparities are largely attributable to non-genetic factors such as socio-economic status, racial discrimination, inadequate health insurance, and unequal exposure to environmental hazards. Still, many believe that genetic research holds a key to explaining and addressing racial/ethnic health disparities. How clinicians translate genetic knowledge into clinical practice, how they integrate genetic and non-genetic illness understandings, and how patients in turn understand this information has not as yet been carefully studied. Using qualitative research techniques of open-ended interviewing and participant observation, the proposed study will explore how a group of primary care clinicians and their patients understand and interpret the genetic and non-genetic basis of two prominent chronic illnesses which differentially impact racial/ethnic minorities diabetes and cardiovascular disease. The study will examine their understandings of susceptibility and management of these diseases. Comparative qualitative analysis will be used to generate specific profiles of ways that genetic information is interpreted and applied by these clinicians and their patients. The study will conclude with a national survey of primary care clinicians, designed to test the generalizability of the qualitative findings, and examine any hypotheses emerging from the analysis. Our specific aims are to 1) Understand how genetic concepts of racial/ethnic difference are interpreted and applied by clinicians serving minority populations. 2) Understand the nature of genetic versus non-genetic factors in clinicians´ understandings of the causes and management of these common chronic illnesses, which differentially impact minority populations. 3) Understand patients´ interpretations of these concepts and of their own risk, health status and treatment responsibility. 4) Generate knowledge of how emerging genetics science can effectively be presented to clinicians and patients, to promote appropriate interpretation and application of genetic knowledge while avoiding possible misinterpretation and racial/ethnic stereotyping. As genetics becomes increasingly central to medical care, there is a clear need for better understanding of how clinicians translate genetic knowledge into their practice, and how patients in turn understand genetic information. This is especially important in assuring appropriate interpretation and application of genetic knowledge concerning diseases that disproportionately affect racial/ethnic minority populations. This project will be contribute valuable insight into clinician and patient use of genetics concepts in everyday clinical encounters, which will yield better understanding of how emerging genetics knowledge can effectively be presented to clinicians and patients, while avoiding possible misinterpretation and racial/ethnic stereotyping
Keywords: ing; Address; Affect; African American; Attention; base; burden of illness; Cardiovascular Diseases; Caring; Chronic; Chronic Disease; Cities; Clinical; clinical practice; comparative; Data Analyses; design; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Management; Environmental Hazards; ethnic minority population; Exposure to; Genetic; Genetic Research; Health; health disparity; Health Insurance; Health Status; Hispanics; Human; Incidence; insight; interest; Interview; Knowledge; Laboratory Research; Life; Medical; Minority; Minority Groups; Nature; non-genetic; Participant; Patients; Policy Maker; Population; Predisposition; Primary Health Care; public health relevance; Qualitative Research; racial and ethnic; racial discrimination; racial/ethnic difference; Research; Research Personnel; Research Technics; Risk; Science of genetics; Socioeconomic Status; Stereotyping; Surveys; Testing; Time; Translating; Translations; treatment adherence
Project start date: 2008-08-29
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01HG004710-03 (2010): $555286
ACTIVATION OF BCL-2 IN HEMATOLOGIC MALIGNANCIES
M Linda, Professor
Palo Alto Institute For Res & Edu, Inc.city: Palo Alto country: United States (us)
Grant 5R01CA056764-17 from National Cancer Institute
Abstract: Follicular lymphoma is characterized by the t(14;18) translocation, which links the bcl-2 gene with the immunoglobulin heavy chain gene (IgH). The translocated bcl-2 allele is expressed at high levels, and the normal allele is silent. The increased levels of Bcl-2 contribute to resistance to chemotherapeutic agents, and follicular lymphoma is rarely cured. We have investigated how the translocated bcl-2 gene is deregulated by the IgH locus and have identified regulatory sites in the bcl-2 promoter and in the 3´ IgH enhancers. The involvement of these sites has been confirmed in an episomal model of the translocation. In this proposal, we will build upon our previous results using a murine model of deregulated bcl-2 expression induced by the IgH 3´ enhancers (IgH-bcl-2 mice). Our studies have provided insight into the mechanisms involved in the deregulation of bcl-2 expression and have also provided evidence that the activation of bcl-2 expression is more complex than previously thought. Based on these results, we propose to more closely examine the regulation of the two bcl-2 promoters in normal B cells and study how one promoter influences the other. In addition, our data demonstrate that while the IgH enhancers are required for the deregulation of bcl-2 expression, they are not sufficient, and that additional changes occur during the transformation process of the B cell. Our investigations will be performed on the bcl-2 gene in the genomic context so that we can study the chromosomal structure at the bcl-2 promoter and define the interactions with the IgH enhancers. Additionally, we will characterize the lymphomas that develop in IgH-bcl-2 mice and compare them to human follicular lymphomas. Information that we gain from the studies on mechanisms involved in bcl-2 deregulation will be utilized to interfere with bcl-2 expression in the IgH-bcl-2 mice as a method to prevent or treat the lymphomas. 1. Characterization of the mechanisms involved in the lack of transcription from the bcl-2 P2 promoter in the absence of the IgH enhancers. 2. Characterization of the molecular mechanisms of bcl-2 deregulation in B cells from IgH-bcl-2 mice to further clarify the mechanisms of bcl-2 deregulation in t(14;18) lymphomas. 3. Development of a preclinical model for t(14;18) lymphomas utilizing the IgH-bcl-2 mice. We are studying a malignancy of B lymphocytes to understand the role of a genetic abnormality involving the bcl-2 gene, which codes for a protein that extends the survival of the malignant cells. Our investigations are designed to determine how the bcl-2 gene is expressed at high levels and to develop a mouse model for the human malignancy (follicular lymphoma). These studies will provide new information that can be used to treat the disease in humans
Keywords: Alleles; B-Lymphocytes; base; BCL1 Oncogene; BCL2 gene; cancer cell; Cell Line; cell transformation; Cells; chemotherapeutic agent; Chromosome Structures; Code; Complex; Data; design; Development; Disease; Enhancers; Follicular Lymphoma; Genetic Transcription; Genomics; Growth; Health; Hematologic Neoplasms; Human; IGH@ gene cluster; insight; Investigation; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Abnormality; mouse model; Mus; Mutate; Mutation; Population; Pre-Clinical Model; Premalignant; prevent; Process; Promotor (Genetics); Proteins; Regulation; research study; Resistance; Role; Sampling; Site; Transgenic Mice
Project start date: 1993-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01CA056764-17 (2011): $281785
MULTIPLE ROLES OF THE API2 MOIETY IN API2-MALT1-MEDIATED LYMPHOMAGENESIS
M Linda, Assistant Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01CA124540-04 from National Cancer Institute
Abstract: Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) accounts for 7- 8% of all non-Hodgkin lymphomas. This tumor arises in sites that are normally devoid of lymphoid tissue, but which acquire organized lymphoid tissue as a result of chronic inflammation prior to the onset of lymphoma. The recurrent chromosomal translocation t(11;18)(q21;q21) occurs in up to 40% of cases and is associated with treatment resistance and tendency to disseminate. This translocation results in the creation of a chimeric protein composed of amino terminal sequences of Inhibitor of Apoptosis 2 (API2) fused to carboxy terminal sequences of MALT1. Despite strong evidence for an important role for t(11;18) in MALT lymphomagenesis, the molecular mechanisms underlying API2-MALT1´s oncogenic activity have not been defined. The studies described in this proposal are aimed at elucidating the role of the API2 moiety in API2-MALT1-dependent oncogenic activity. We hypothesize that the API2 moiety of API2-MALT1 contributes to oncogenesis by mediating oligomerization of the fusion protein and by interacting with critical signaling proteins that regulate cell survival. We will use a combination of biochemical studies, cellular transformation analyses and mouse models to test this hypothesis. This research will further our understanding of the complex relationship between inflammation and cancer. The anticipated results will provide significant insight into the molecular pathogenesis of MALT lymphoma and will pave the way toward the development of novel rational therapies for refractory disease
Keywords: Accounting; Animal Model; Antineoplastic Agents; Apoptosis; Apoptosis Inhibitor; B-Cell Lymphomas; base; Binding (Molecular Function); Biochemical; Bone Marrow; caspase; Cell Survival; Chimeric Proteins; Chromosomal translocation; Chronic; Complex; design; Development; Extranodal; Family member; human BIRC3 protein; in vivo; Inflammation; innovation; insight; Lymphocyte; Lymphoid Tissue; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; metaplastic cell transformation; Modeling; Molecular; mouse model; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; Mus; Non-Hodgkin`s Lymphoma; novel; novel therapeutics; Oncogenic; Pathogenesis; protein protein interaction; Recurrence; Refractory; Refractory Disease; Research; Resistance; Role; Signal Transduction; Signaling Protein; Site; small molecule; t(11;18)(q21;q21); Testing; Therapeutic Agents; TRAF2 gene; Transplantation; tumor; tumorigenesis
Project start date: 2008-09-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01CA124540-04 (2011): $309532
EARLY LIFE EXPERIENCE SHAPES VISCERAL CIRCUITS
M Linda, Associate Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R01MH081817-03 from National Institute Of Mental Health
Abstract: Early life experience can alter adult emotionality and stress responsiveness, but only limited research has examined how experience shapes the development of central neural circuits. We predict that manipulation of early life experience will alter the functional organization of central visceral circuits, and that altered neuroanatomy will correspond with altered behavioral, physiological, and neural responses to stressful events. The proposed research will test this prediction by performing experiments in adult male and female rats with a developmental history of having been handled briefly for daily maternal separation of either 15 min (MS15) or 3 hr (MS180) during the first two postnatal weeks. Non-separated (MS0) rats will serve as controls. As young adults, all rats will be screened for behavioral differences in the elevated plus maze, and blood samples will be collected to document restraint stress-evoked excursions in plasma corticosterone. Subsequent experiments in Aims 1 and 2 will be performed in behaviorally- and hormonally-screened adult rats. Aim 1 experiments will test the hypothesis that early maternal care (manipulated via MS15 and MS180) interacts with sex to differentially alter the anatomical features of central visceral circuits. Retrograde transneuronal transport of pseudorabies virus will be used to probe for differences in central autonomic circuits in rats with different developmental histories. In the second experiment, experience-dependent alterations in noradrenergic (NA) sensory pathways will be examined. For this, a unique lentivirus vector that expresses enhanced green fluorescent protein under the control of a dopamine beta hydroxylase promoter will be microinjected into the caudal medulla to label the axonal arbors of transfected NA neurons that project to the hypothalamus and limbic forebrain. Aim 2 experiments will test the hypothesis that early maternal care interacts with sex to differentially alter stressor-induced neural Fos activation in central visceral circuit nodes. Rats will be perfused with fixative after restraint, LiCl treatment, predator odor exposure, or matched control treatment for analyses of stimulus-induced Fos expression in medullary NA neurons and in their central projection fields. NA terminal immunolabeling density and CRF/CRH labeling also will be quantified to determine whether sex and/or MS group differences interact. Data will be analyzed and interpreted within the context of behavioral and hormonal responses in the screening tests, with attention paid to predicted effects of early postnatal experience and sex on anatomical and physiological outcomes. The proposed work will advance our understanding of how early maternal care can alter the developmental trajectory of central visceral circuits in males and females, and will provide new insights regarding the impact of early experience on adult emotionality and stress responsiveness. Interactions between infants and their mother (or primary caregiver) are critical for normal growth and development, and perturbations can disrupt physiological and behavioral functions in the offspring. The proposed research will use anatomical and physiological methods in rats to test the hypothesis that the influence of early life events on later responses to stress and emotional events is linked to developmental plasticity of circuits that provide visceral sensory feedback to the brain and generate emotional expression
Keywords: Acute; acute stress; Address; Adult; Affect; Animal Experimentation; animal facility; Anxiety; Attention; Behavior; Behavioral; Biological Assay; Blood specimen; Brain; Brain Stem; Caregivers; Caring; comparative; Corticosterone; CRH gene; Data; density; Development; developmental plasticity; Disease; Dopamine-beta-monooxygenase; early experience; Emotional; Emotional Stress; Emotions; enhanced green fluorescent protein; Epigenetic Process; Event; experience; Exposure to; Female; Fixatives; Fright; Growth and Development function; Health; Hormonal; Human; Hypothalamic structure; Individual; Infant; insight; Label; Laboratory Rat; Learning; Lentivirus Vector; Life; Life Experience; Link; Lithium Chloride; male; maternal separation; Methods; Modeling; Monitor; Mothers; Motivation; Motor; neural circuit; Neuroanatomy; Neurons; neuroregulation; noradrenergic; Odors; offspring; Outcome; Pathway interactions; Physiological; Plasma; postnatal; Price; Promotor (Genetics); Prosencephalon; pup; Rattus; Recording of previous events; relating to nervous system; Reporting; Research; research study; response; restraint; restraint stress; Screening procedure; Sensory; sensory feedback; Septic Toxemia; sex; Sex Characteristics; Sexual Maturation; Shapes; showing emotion; Signal Transduction; Stimulus; Stress; Stressful Event; stressor; Suid Herpesvirus 1; Testing; tissue fixing; Variant; Visceral; Weaning; Work; young adult
Relevance: Interactions between infants and their mother (or primary caregiver) are critical for normal growth and development, and perturbations can disrupt physiological and behavioral functions in the offspring. The proposed research will use anatomical and physiological methods in rats to test the hypothesis that the influence of early life events on later responses to stress and emotional events is linked to developmental plasticity of circuits that provide visceral sensory feedback to the brain and generate emotional expression
Project start date: 2009-03-20
Project end date: 2014-01-31
Budget start date: 23-MAR-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01MH081817-03 (2011): $246365
UNFOLDED PROTEIN RESPONSE IN DRUG SENSITIVITY AND RESISTANCE
M Linda, Member
St. Jude Children´s Research Hospitalcity: Memphis country: United States (us)
Abstract: Due to inadequate blood supply, tumor cells exist in a compromised microenvironment that impinges on normal protein folding and can activate the unfolded protein response (DPR). In addition to contributing to tumor growth and survival, data from cell culture studies demonstrate that pharmacological activation of the UPR can also alter the sensitivity of cells to chemotherapeutic agents, making them more sensitive in some cases and more resistant in others. In the previous cycle of funding, we showed that UPR activation is both necessary and sufficient to reduce the sensitivity to topoisomerase II targeted therapy and found that this is a result of PERK activation. We propose genetic analyses in the coming cycle to identify the responsible target(s) and determine to what extent the UPR affects drug sensitivity in xenograft studies. Conversely, UPR activation increases the sensitivity of cells to cisplatin, which damages both DMA and proteins. As a number of anti-cancer agents have similar characteristics, we propose to explore interactions between these agents and the UPR and to determine the mechanism or interaction where synergies exist. Given the broad affects of the UPR on cellular processes, it is likely that this pathway will interact with other chemotherapeutic agents. Indeed, our preliminary data demonstrate that activation of the UPR reduces the sensitivity of cells to the topoisomerase I poison, topotecan. Finally, anti-angiogenic agents are being used to inhibit tumor vascularization, which should contribute to UPR activation in the tumor. However, recent data demonstrate that they can also promoter vascular remodeling, making it unclear how this will affect UPR activation. Since the UPR leads to both increased transcription and processing of pro-angiogenic factors, it is essential to understand the affect of anti-angiogenic agents on the UPR and to determine if the UPR plays a role in resistance to these agents. In this proposal, we describe experiments to determine the mechanisms by which the UPR increases sensitivity to some agents while decreasing sensitivity to others, explore possible interactions with additional chemotherapeutic agents, and determine the affect of UPR activation on drug sensitivity in animal models. In addition, we will extend our initial examination of UPR activation in tumor samples to other UPR targets and multiple types of tumors to establish the scope of the significance of our findings to pediatric cancers
Keywords: Affect; Aftercare; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Animals; Antineoplastic Agents; antitumor agent; Apoptotic; arm; Beryllium; Buffers; Carmustine; Cell Culture Techniques; Cell Cycle Arrest; cell killing; Cell physiology; Cells; Characteristics; chemotherapeutic agent; Childhood Solid Neoplasm; Cisplatin; clinically relevant; Collaborations; Coupled; Data; DNA Damage; Doctor of Philosophy; drug efficacy; Drug resistance; drug sensitivity; Elements; Embryo; Engineering; experience; Fibroblasts; Funding; Gene Targeting; genetic analysis; Genetic Transcription; Human; Knock-out; Malignant Childhood Neoplasm; Mediating; Molecular Chaperones; molecular pathology; Mus; neoplastic cell; Pathway interactions; Pediatric Neoplasm; Pharmaceutical Preparations; Play; Poisons; Process; programs; Promotor (Genetics); protein folding; Proteins; Regulatory Element; Research Personnel; research study; Resistance; response; Role; Sampling; Stress; temozolomide; Testing; Tissue Array Analysis; Topoisomerase II; Topotecan; Toxic effect; Transcription Process; tumor; tumor growth; Type I DNA Topoisomerases; Up-Regulation (Physiology); Vascular blood supply; Vascular Endothelial Growth Factors; Vascular remodeling; Vascularization; Xenograft Model; Xenograft procedure
Project start date: 2011-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P01CA023099-33_0013 (2011): $282152
Sponsored Links Excellgen http://Excellgen.com
HMGA1 IN TUMOR PROGRESSION IN BREAST CANCER
M Linda, Associate Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R21CA149550-02 from National Cancer Institute
Abstract: Despite progress in the detection and treatment of metastatic breast cancer, mortality from this disease remains high because current therapies are limited by the emergence of cancer cells that are resistant to treatment and capable of metastatic progression. Increasing evidence suggests that these cells develop, in part, because they behave like stem cells and thereby evade cell death induced by therapies which target rapidly dividing tumor cells. This proposal is directed at elucidating molecular pathways important in metastatic progression and "stemness" in breast cancer with the goal of identifying novel therapeutic targets and biomarkers. Our focus is the HMGA1 oncogene because recent findings suggest that it plays a critical role in both of these processes. This gene encodes the HMGA1a and HMGA1b chromatin binding proteins, which function in modulating gene expression. HMGA1 is highly expressed during embryogenesis, but not in adult tissues. Strikingly, HMGA1 is also overexpressed in virtually all high-grade (poorly differentiated) human cancers studied to date. We first established that HMGA1 induces oncogenic transformation in cultured cells derived from normal breast cells. HMGA1 also causes aggressive cancers in transgenic mice and promotes an epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cells. Conversely, inhibiting its expression blocks transformation phenotypes in high-grade, human breast cancer cell lines and prevents metastatic progression in some tumor models. A recent study also found that HMGA1 is among a list of 9 core transcription factors enriched in high-grade/poorly differentiated breast cancers and normal embryonic stem cells, further implicating HMGA1 as a key regulator in breast cancer progression and stem cells. Taken together, these findings suggest that HMGA1 orchestrates transcriptional networks that maintain a primitive, poorly differentiated state, both in breast cancer and stem cells. Based on these findings, we hypothesize that HMGA1 drives tumor progression by inducing transcriptional networks that maintain an undifferentiated, "stem-like" phenotype. Here, we propose studies to determine if HMGA1 is a biomarker and potential therapeutic target in metastatic breast cancer. We will also begin studies to determine how HMGA1 drives tumor progression in breast cancer. Using our unique resources, we propose the following Specific Aims 1.) Determine if HMGA1 can serve as a biomarker for more advanced, less differentiated breast cancer using a tissue microarray with primary breast tumors and detailed clinical data from >500 patients, 2.) Elucidate the role of HMGA1 in tumor progression and the stem-cell phenotype using gain-of- function/loss-of-function approaches, and, 3.) Identify the molecular signature of HMGA1 in metastatic breast cancer and begin to define the functional significance of downstream transcriptional targets. Results from our studies will elucidate novel molecular circuitry important in tumor progression and should lead to the discovery of cellular pathways that could be targeted in therapy for metastatic breast cancer. Although metastatic breast cancer is a common and highly lethal cancer that affects women worldwide, the cellular pathways that mediate tumor progression and resistance to therapy are poorly understood. To address this knowledge gap, we propose to study the HMGA1 oncogene, which is highly expressed in advanced breast cancer and embryonic stem cells. Results from our studies should enhance our understanding of how breast cancer progresses and provide the basis to design better therapies directed at these resistant cells
Keywords: Address; Adult; Affect; American; anticancer research; Automobile Driving; base; Binding Proteins; biomarker; Breast; Breast Cancer Cell; Breast Cancer Detection; Cancer Biology; cancer cell; Cancer cell line; Cancer Etiology; Cancer Model; Cancer stem cell; CD44 gene; Cell Culture Techniques; Cell Death; Cell Line; Cells; cellular transduction; Cessation of life; Chromatin; Clinical; Clinical Data; coping; Cultured Cells; Data; design; Detection; Development; Diagnosis; Disease; Embryonic Development; embryonic stem cell; Ensure; epithelial to mesenchymal transition; ERBB2 gene; experience; gain of function; Gene Expression; Gene Targeting; Genes; Genetic Programming; Goals; Grant; HMGA1 gene; HMGA1b Protein; Human; human disease; Image; Immunodeficient Mouse; immunoreactivity; in vivo; Injection of therapeutic agent; innovation; knock-down; Knowledge; Koreans; Lead; loss of function; Lung; malignant breast neoplasm; Malignant Neoplasms; Mammary Neoplasms; MCF7 cell; Mediating; Messenger RNA; MicroRNAs; migration; Modeling; Molecular; Molecular Profiling; Mortality Vital Statistics; multidisciplinary; Mus; Neoplasm Metastasis; neoplastic cell; new therapeutic target; Normal tissue morphology; novel; Oncogenes; Oncogenic; Oncologist; Outcome; outcome forecast; overexpression; P-Cadherin; Pathologist; Pathway interactions; Patients; Phenotype; Play; Population; Positioning Attribute; prevent; Primary Neoplasm; Process; Proteins; public health relevance; Reagent; Research Personnel; Resistance; Resources; Role; Sampling; Specimen; Staging; Staphylococcal Protein A; stem; Stem cells; stemness; success; Tail; therapeutic target; therapy resistant; Tissue Microarray; Tissues; tool; transcription factor; Transgenic Mice; tumor; tumor progression; Tumor Tissue; Tumorigenicity; Undifferentiated; Veins; Veterinarians; Woman; Work; Xenograft procedure
Relevance: Although metastatic breast cancer is a common and highly lethal cancer that affects women worldwide, the cellular pathways that mediate tumor progression and resistance to therapy are poorly understood. To address this knowledge gap, we propose to study the HMGA1 oncogene, which is highly expressed in advanced breast cancer and embryonic stem cells. Results from our studies should enhance our understanding of how breast cancer progresses and provide the basis to design better therapies directed at these resistant cells
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-267
5R21CA149550-02 (2011): $173000
CENTRAL VISCEROSENSORY CIRCUITS - STRUCTURE AND FUNCTION
M Linda, Associate Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R01MH059911-13 from National Institute Of Mental Health
Abstract: Clinical research has increasingly emphasized the importance of ascending viscerosensory pathways from the caudal brainstem, including noradrenergic (NA) pathways, in stress responses and affective/emotional state. Dysregulated NA signaling is implicated in the pathophysiology of stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of ascending NA pathways that modulate neural activity within interconnected regions of the paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and anterolateral bed nucleus of the stria terminalis (alBST). These pathways arise from NA neurons in viscerosensory regions of the nucleus of the solitary tract (NST) and ventrolateral medulla (VLM), with little or no direct contribution from the pontine locus coeruleus. Revealing the functional organization of these systems in rats has clinical relevance, and may contribute to the development of new therapeutic options for treating stress-related emotional dysregulation. Our working hypothesis is that both physiological (interoceptive) and cognitive/emotional stressors alter viscerosensory signals that are relayed by medullary NA neurons to the hypothalamus and limbic forebrain, and that these signals are critical for shaping emotional state as evidenced by stress responsiveness, motivated behavior, and emotional learning. NA neurons within the NST and VLM have branching axons that target more than one hypothalamic and limbic forebrain target. Retrograde tract-tracing experiments in Aim 1 will simultaneously examine NA axonal collateralization and ascending pathway recruitment by a malaise- inducing agent, lithium chloride (LiCl). The anatomical data obtained in Aim 1 will facilitate interpretation of functional data obtained in Aim 2, in which NA inputs to the PVN, CeA, and/or alBST will be selectively destroyed before rats are assayed for behavioral and physiological responses to three distinct challenges (1) LiCl, (2) exposure to a fear- and anxiety-inducing predator odor, trimethylthiazoline (TMT), or (3) systemic yohimbine (YO), a pharmacological agent that robustly increases NA signaling throughout the brain. Parallel experiments in Aim 3 will test the hypothesis that direct communication between the CeA and alBST is necessary for behavioral and physiological responses to LiCl, TMT, and YO in rats with otherwise intact central NA circuitry. The proposed research will reveal new aspects of the functional organization of viscerosensory NA inputs to the hypothalamus and limbic forebrain that play a critical role in mediating physiological and behavioral responses to emotionally significant events. Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies
Keywords: Affective; Amygdaloid structure; Anterolateral; Anti-Dopamine-b-Hydroxylase Monoclonal Antibody-Saporin; antibody conjugate; Anxiety; Anxiety Disorders; Axon; Behavior; Behavioral; Behavioral Assay; Bilateral; biological adaptation to stress; Brain; Brain Stem; Cell Nucleus; Clinical Research; clinically relevant; Cognitive; Communication; Contralateral; Data; Development; Dopamine-beta-monooxygenase; Emotional; Emotions; Endocrine; Event; Excitatory Neurotoxins; Experimental Models; Exposure to; Feedback; Fright; Functional disorder; Human; Hypothalamic structure; ibotenate; Lead; Learning; Left; Lesion; Lithium Chloride; locus ceruleus structure; Malaise; Medial; Mediating; Mental Depression; motivated behavior; Neurons; noradrenergic; novel therapeutics; Nucleus solitarius; Odors; Outcome; paraventricular nucleus; parvocellular; Pathology; Pathway interactions; Physiological; Play; Pontine structure; Prosencephalon; Rattus; Recruitment Activity; relating to nervous system; Research; research study; response; Role; Shapes; Side; Signal Transduction; Stimulus; Stress; stressor; Structure; Structure of terminal stria nuclei of preoptic region; Sympathomimetics; System; Testing; Toxin; Visceral; Work; Yohimbine
Relevance: Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies
Project start date: 1999-04-01
Project end date: 2014-02-28
Budget start date: 1-APR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01MH059911-13 (2011): $1
AFRICAN DESCENT AND GLAUCOMA EVALUATION (ADAGES) II: GLAUCOMA PROGRESSION
M Linda, Adjunct Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01EY019869-02 from National Eye Institute
Abstract: African Descent and Glaucoma Evaluation Study (ADAGES) II To identify what ocular and systemic factors account for the differences in the occurrence of vision loss and structural damage and the more rapid rate of progression found for individuals of African Descent (AD) compared to those of European Descent (ED) and to account for these differences when developing algorithms for predicting progression. The specific aims are 1) To quantify differences in progressive loss of visual function and structural damage between AD and ED patients with glaucoma, 2) To quantify differences in the rate of progressive visual loss and structural damage between AD and ED patients with glaucoma, and most importantly, 3) To combine information from structural imaging, visual function testing, clinical information and risk factors to develop and validate a multivariate model of improve detection and prediction of progressive glaucomatous damage. Design A prospective, multi-center observational cohort study to obtain the additional follow-up needed to meet the project´s objective. Participants are 618 AD and ED participants with glaucoma who were part of the cohort for ADAGES I, which focused on identifying differences due to ancestry that are important for diagnosing glaucoma, documenting stage of disease, and understanding the relationship among retinal structure and visual function. Data from an additional 323 ED participants is available from another the Diagnostic Innovations in Glaucoma Study (DIGS). Demographic variables, ophthalmological examination including stereophotographs, ocular, systemic, and other risk factors will be documented. Visual function with standard perimetry and optic nerve structure with the Heidelberg Retina Tomograph will be assessed at six-month intervals. Impact Glaucoma, the leading cause of blindness in African Americans, is four to five times more likely to occur and to progress to severe visual impairment in persons of AD compared to persons of ED. Significant differences were found in a number of clinical and test findings between persons of AD compared to ED in ADAGES I. The additional longitudinal data from ADAGES II will provide critical longitudinal data to develop and validate multivariate prediction models of glaucomatous progression with input from quantitative optic nerve and retinal imaging and visual functional testing. ADAGES II will provide clinicians with critical information on the risk of progressing glaucoma in individual patients, information that can substantially improve the effectiveness of individualized treatment for this potentially blinding disease. African Descent and Glaucoma Evaluation Study (ADAGES) II Glaucoma is four to five times more likely to occur in persons of African descent, up to fifteen times more likely to cause meaningful visual impairment in this group compared to those of European descent and the leading cause of blindness in African Americans. ADAGES II will develop models to predict which individuals are most at risk for progression of glaucoma using knowledge gained about the factors associated with change in visual function and retinal structure, including ancestry, stage of disease, and rate of change. This will provide clinicians with critical information currently not known or well understood information that will substantially improve the effectiveness of individualized treatment for this potentially blinding disease
Keywords: Accounting; Active Follow-up; Address; African; African American; Afro American; Afroamerican; Age; Alabama; Algorithms; base; black American; Black or African American; Black Populations; Blindness; California; Caring; Characteristics; Clinical; Clinical Research; Clinical Study; cohort; Cohort Studies; computer based prediction; Concurrent Studies; Cornea; corneal; cost; Cranial Nerve II; Cranial Nerve II Diseases; Cranial Nerve II Disorder; Data; Data Collection; Data Coordinating Center; Data Coordination Center; design; designing; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; disease severity; disease/disorder; Disorder; Disorder of the optic nerve; Doctor of Medicine; Doctor of Philosophy; drug/agent; Drugs; Dysfunction; Ear; Ear structure; Effectiveness; enroll; Enrollment; European; Evaluation; Evaluation Studies; Event; Eye; Eyeball; follow-up; Functional disorder; Functional Imaging; Funding; Glaucoma; glaucomatous; Goals; high risk; History; Image; imaging; Imaging Device; Imaging Tool; improved; Individual; innovate; innovation; innovative; Intervention; Intervention Strategies; interventional strategy; Investigators; Knowledge; Length; Literature; long-term study; Longitudinal Studies; M.D.; Manuals; Measurement; Measures; Medication; meetings; Methods; Minority; Modeling; Monitor; Natural History; Nerve Fibers; Neural-Optical Lesion; New York; Ophthalmology; Optic Disk; Optic Nerve; Optic Nerve Diseases; optic nerve disorder; Optic Nerve Head; Optic Neuropathy; Optic Papilla; Partial Sight; Participant; pathophysiology; patient population; Patients; Pattern; Perimetry; Persons; Ph.D.; Pharmaceutic Preparations; Pharmaceutical Preparations; PhD; Physiologic Imaging; Physiopathology; POAG; Population; population based; predictive modeling; Prevalence; Primary Open Angle Glaucoma; Procedures; Process; Progressive Disease; prospective; Prospective Studies; Protocol; Protocols documentation; public health relevance; Race; Racial Group; Reading; Recording of previous events; Reporting; Research; Research Design; Research Personnel; Researchers; Retina; Retinal; retinal nerve fiber layer; Risk; Risk Factors; Saint Lucia; Sample Size; Sampling; Second Cranial Nerve; Second Cranial Nerve Diseases; second cranial nerve disorder; Severity of illness; Sight; Site; Specialist; St. Lucia; Staging; Stocks, Racial; Stress; Structure; study design; Study Type; SUBGP; Subgroup; Testing; Thick; Thickness; Time; tool; Universities; Vision; Vision, Diminished; Vision, Low; Vision, Reduced; Vision, Subnormal; Visit; Visual; Visual Fields; Visual impairment; visual optics; visually impaired
Relevance: African Descent and Glaucoma Evaluation Study (ADAGES) II: Progression Glaucoma is four to five times more likely to occur in persons of African descent, up to fifteen times more likely to cause meaningful visual impairment in this group compared to those of European descent, and the leading cause of blindness in African Americans. ADAGES II will develop models to predict which individuals are most at risk for progression of glaucoma using knowledge gained about the factors associated with change in visual function and retinal structure, including ancestry, stage of disease, and rate of change. This will provide clinicians with critical information currently not known or well understood, information that will substantially improve the effectiveness of individualized treatment for this potentially blinding disease
Project start date: 2010-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01EY019869-02 (2011): $444485
STATE BASED ORAL HEALTH DISEASE PREVENTION PROGRAM TEXAS
M Linda
Texas State Dept Of Health Servicescity: Austin country: United States (us)
Grant 1U58DP002840-01 from National Center For Chronic Disease Prev And Health Promo
Project start date: 2010-09-01
Project end date: 2013-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-DP-10-012
1U58DP002840-01 (2010): $242128