STANFORD NEUROSURGERY RESIDENT RESEARCH EDUCATION PROGRAM
K Gary
Stanford Universitycity: Stanford country: United States (us)
Grant 5R25NS065741-04 from National Institute Of Neurological Disorders And Stroke
Keywords: Basic Science; Behavior; Brain Diseases; career; career development; Clinical Research; Counseling; Disease; Educational aspects; effective therapy; Ethics; experience; Fostering; Funding; Goals; Growth; Health; improved; Investigation; Laboratories; Mission; Neurologic; Neurosurgeon; neurosurgery; Persons; programs; public health relevance; Research; Scientist; skills; Spinal Cord; success; Training; Translational Research; United States National Institutes of Health
Relevance: This project seeks support for the education of neurosurgical residents in research. It is hoped that this will produce neurosurgeons capable on making new discoveries regarding the causes of diseases of the brain and spinal cord and that new, more effective treatments will result
Project start date: 2009-03-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2012
Budget end date: 28-FEB-2013
5R25NS065741-04 (2012): $1
Sponsored Links Excellgen http://Excellgen.com
STANFORD NEUROSURGERY RESIDENT RESEARCH EDUCATION PROGRAM
K Gary
Stanford Universitycity: Stanford country: United States (us)
Grant 5R25NS065741-03 from National Institute Of Neurological Disorders And Stroke
Abstract: Project The purpose of this Stanford Neurosurgery Resident Research Education Program is to provide education in basic and clinical research to neurosurgery residents with the goal of fostering their growth into clinician scientists. Its goal is to educate and train neurosurgeons capable of establishing and directing a scientific laboratory throughout their careers. The strategy is to identify residents with the potential for scientific research and place them for a two year term in the laboratories of senior, highly experienced research scientists. They will also receive extensive counseling by the neurosurgical directors of the program and participate in seminars on research skills and ethical research behavior. Their progress and the success of the overall program will be repeatedly assessed and appropriate changes in the program will be made. It is hoped that this program will produce neurosurgeons capable of making new discoveries regarding the causes of diseases of the brain and spinal cord, that new, more effective treatments will result, and, in fulfillment of the mission of the NIH, that the health of persons afflicted with these diseases will be improved. This project seeks support for the education of neurosurgical residents in research. It is hoped that this will produce neurosurgeons capable on making new discoveries regarding the causes of diseases of the brain and spinal cord and that new, more effective treatments will result
Keywords: Basic Science; Behavior; Brain Diseases; career; career development; Clinical Research; Counseling; Disease; Educational aspects; effective therapy; Ethics; experience; Fostering; Funding; Goals; Growth; Health; improved; Investigation; Laboratories; Mission; Neurologic; Neurosurgeon; neurosurgery; Persons; programs; public health relevance; Research; Scientist; skills; Spinal Cord; success; Training; Translational Research; United States National Institutes of Health
Relevance: This project seeks support for the education of neurosurgical residents in research. It is hoped that this will produce neurosurgeons capable on making new discoveries regarding the causes of diseases of the brain and spinal cord and that new, more effective treatments will result
Project start date: 2009-03-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: RFA-NS-09-001
5R25NS065741-03 (2011): $1
5R25NS065741-02 (2010): $1
Grants awarded to K Gary
SHORT-TERM TRAINING TO INCREASE DIVERSITY IN HEALTH-RELATED RESEARCH
K Gary, Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5R25HL088724-05 from National Heart, Lung, And Blood Institute
Abstract: We propose to continue an existing and highly successful Summer Research Internship Program (SRIP) at the University of Virginia School of Medicine. The goals of this program will be to expose a diverse group of undergraduate students and medical students to state of the art cardiovascular research, to instill in them confidence and a desire to consider research as a career option, and to familiarize them with the opportunities that exist for a career in biomedical research. The program runs for ten weeks each summer and is multi-faceted. The first and most important facet involves student exposure to and participation in a contemporary research project under the guidance of a faculty member. A second facet has the students participating in a series of weekly workshops in which students are exposed to a variety of advanced research techniques that they are unlikely to see in individual laboratories, including the use of confocal and electron microscopy, bioinformatics, genomics and proteomics, genetic mapping techniques, hybridoma/monoclonal antibody preparation, etc. The third facet includes a series of lectures and discussions wherein the students are exposed to a wide array of research topics and internationally recognized scientists. These scientists include women and underrepresented minority scientists who can serve as role models for these students. Finally, a fourth facet of our program is a weekly research lunch co- hosted by the Dr. Owens and the co-principal investigator, Dr. Hockensmith, during which the students give oral statements of their working hypotheses, summaries of the past week´s research progress, discuss career options and opportunities, and consider approaches for choosing and applying to a graduate program. More than sixty faculty members, with research interests in cardiovascular-related areas, will serve as mentors. All components of this program are currently in place. The program has an exceptional pool of highly qualified candidates (>250 total/120 URM) for 2006, and the matriculants had an average GPA of 3.6 during the current funding cycle. In summary, we feel that our program provides an outstanding environment to stimulate and foster interest in research careers in biomedical research. Reviews of the program by past participants have been outstanding and have contributed significantly to the continued interest in our program
Keywords: Admission activity; Advertising; Amino Acid Sequence; Area; Award; Awareness; Back; Bioinformatics; Biological; biomathematics; Biomedical Engineering; Biomedical Research; Biotechnology; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; career; Cellular biology; Chemicals; Chromosome Mapping; Clinical; clinical practice; college; Commit; Communicable Diseases; Confocal Microscopy; cost; Cost Sharing; Data; Development; digital imaging; DNA; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Electron Microscopy; Engineering; Environment; Expenditure; experience; Exposure to; Extramural Activities; Faculty; Fostering; Funding; Future; General Population; Generations; Genomics; Goals; Government; Grant; Growth; Head; Health; Hybridomas; Hylobates Genus; Imaging Techniques; Indium; Individual; Industry; insight; Interdisciplinary Study; interest; Internships; Laboratories; Laboratory Research; lecturer; lectures; Literature; Medical; medical schools; Medical Students; Medicine; meetings; member; men; Mentors; Microcirculation; Minority; Molecular Biology; Molecular Cytogenetics; Monoclonal Antibodies; monoclonal antibody production; Motivation; National Heart, Lung, and Blood Institute; Nature; Neurosciences; Oral; Participant; peer; Pharmacologic Substance; Play; Population; posters; Preparation; Principal Investigator; Printing; Process; Program Reviews; programs; Progress Reports; Proteins; Proteomics; Published Comment; Qualifying; racial and ethnic; Radiation; Regulation; Reporting; Research; Research Institute; Research Project Grants; research study; Research Technics; Research Training; Resources; Role; role model; Running; Safety; satisfaction; Scanning Transmission Electron Microscopy Procedures; Schedule; Scholarship; Schools; Scientist; Series; Shadowing (Histology); Students; success; Surgeon; Techniques; Technology; Time; Training; Training Activity; Training Programs; Transgenic Mice; Translational Research; Underrepresented Minority; United States National Institutes of Health; United States Public Health Service; Universities; Vaccines; Virginia; Wages; Woman; Women`s Health; Work; X-Ray Crystallography
Project start date: 2007-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-HL-05-018
5R25HL088724-05 (2011): $97902
STANFORD NEUROSCIENCE RESEARCH CORES FOR GENE VECTORS, MICROSCOPY, AND BEHAIVOR
K Gary, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 1P30NS069375-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: This proposal seeks to establish essential core research facilities to meet the following identified shared needs of the Stanford Neuroscience research community (1) gene vector and virus production, (2) advanced microscopy data acquisition and analysis, and (3) automated behavioral phenotyping. Viral vectors are used to express recombinant proteins and/or knock down expression of endogenous proteins in specific subsets of cells in brain tissue. It is even possible to express proteins that enable precise temporal control over the activity of individual neurons. Use of such viral tools is revolutionizing neuroscience research. A centralized core facility will vastly improve the efficiency and cost-effectiveness of virus production. Three dimensional image analysis and visualization are essential for quantifying information from volume imaging techniques, such as Array Tomography, and single- and two-photon confocal microscopy. Software and hardware for this type of analysis is expensive, and has a steep learning curve. This proposal will fund the Image Analysis Center, a central resource with technical expertise to assist scientists with image analysis problems, and an electrophysiological recording setup for an existing shared two-photon tissue slice rig- standardized, replicable behavioral tests are critical to translating progress from basic neuroscience research to treatments relevant to human disease. Automated behavioral phenotyping can provide more consistent results by eliminating stress due to removal from the home cage and novelty effects from the test environment. Automated testing can also Improve throughput and reduce costs. This proposal will provide funds to expand capacity for automated behavioral testing in an existing core facility. These core facilities will be a central part of SINTN´s effort to advance our understanding of normal brain and spinal cord function at the molecular, cellular, and neural circuit level, and to elucidate the pathological processes underlying malfunction of the nervous system following injury or neurologic and psychiatric diseases. Creating core services to meet these shared research needs will foster efficiency and productivity by minimizing the unnecessary duplication of equipment and creating a centralized source of expertise for shared tasks with the net effect of better solutions in less time. Moreover, the resulting formal and informal collaborations will provide the foundation for a richer, stronger, and more vibrant research community. RELEVANCE This proposal will establish core research facilities for use by Stanford Neuroscience faculty. These facilities will enable researchers to more rapidly assess the functions of specific proteins involved in brain disease, brain development, or recovery from brain injury, and provide the means to assess functional changes in individual neuronal cells, in circuits made from groups of cells, and in the behavior of laboratory animals
Project start date: 2011-03-01
Project end date: 2015-11-30
Budget start date: 1-MAR-2011
Budget end date: 30-NOV-2011
PFA/PA: PAR-08-116
1P30NS069375-01A1 (2011): $772554
ROLE OF OXIDIZED PHOSPHOLIPIDS IN PHENOTYPIC SWITCHING OF SMOOTH MUSCLE CELLS (SM
K Gary, Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5R01HL087867-04 from National Heart, Lung, And Blood Institute
Abstract: There is clear evidence that phenotypic switching of the vascular smooth muscle cell (SMC) plays a critical role in development of atherosclerotic disease, and end stage clinical consequences such as plaque rupture/thrombosis. However, the mechanisms and factors that regulate SMC phenotypic switching in atherogenesis are poorly understood. In addition, although there is compelling evidence that oxidized phospholipids (oxPLs) play a critical role in activation of endothelial cells and monocytes/macrophages during atherogenesis, virtually nothing is known regarding the role of oxPLs in control of phenotypic switching of vascular SMC. The focus of this proposal is to test the hypothesis that oxidized 1-palmitoyl-2-arachidonoyl-sn- glycero-3-phosphorylcholine (OxPAPC) and its oxPL components POVPC and PGPC play a key role in regulating SMC phenotypic switching associated with experimental vascular injury/atherogenesis, and that the effects of these compounds are mediated at least in part through the G/C repressor/TCE binding protein KLF4 and ERK-dependent phosphorylation of ELK1. In support of this hypothesis, we found that oxPAPC, POVPC, and PGPC profoundly suppressed expression of all SMC differentiation marker genes tested to date including SM a-actin, SM myosin heavy chain (MHC), and myocardin in cultured SMC, as well as in carotid arteries in vivo. In contrast, oxPLs increased expression of KLF4, a gene we have previously shown can markedly suppress expression of the potent SMC selective SRF co-activator myocardin (and myocardin like factors), and induce histone modifications of SMC marker gene loci associated with chromatin condensation and transcriptional silencing. In addition, we present preliminary data showing that POVPC-induced suppression of SMC differentiation marker genes in cultured SMC and in vivo can be inhibited by siRNA-induced suppression of KLF4. Aim 1 will determine mechanisms by which oxPLs suppress expression of SMC differentiation marker genes such as SM a-actin, SM MHC, and SM22a and will include investigation of the role of inhibition of CArG-SRF-myocardin dependent transcription by KLF4 and phospho-ELK1. Aim 2 will determine the role and mechanisms by which oxPLs regulate SMC phenotypic switching in vivo in response to vascular injury and/or experimental atherosclerosis using a novel pluronic gel system developed in our labs in combination with unique SMC promoter-reporter transgenic mice, and conditional KLF4/ApoE knockout mice. Taken together, studies will provide novel insights regarding cellular and molecular mechanisms whereby oxPLs contribute to phenotypic switching of SMC in atherogenesis, and may lead to development of novel therapies for inhibiting atherosclerotic lesion formation, progression, and/or plaque rupture
Keywords: Actins; Address; AGEPC receptor; Antigens, Differentiation; ApoE knockout mouse; Arterial Fatty Streak; Assay; atherogenesis; Atheroma; atheromatosis; Atheromatous; Atheromatous degeneration; Atheromatous plaque; Atheroscleroses; Atherosclerosis; atherosclerosis plaque; Atherosclerotic Cardiovascular Disease; atherosclerotic lesions; atherosclerotic plaque; atherosclerotic vascular disease; balance; balance function; Binding; Binding (Molecular Function); Binding Proteins; Bioassay; Biologic Assays; Biological Assay; Blood monocyte; Blood Vessels; Blotting, Western; Boxing; calponin; Carotid Arteries; CCL2; CCL2 gene; Cell Culture System; Cell Differentiation; Cell Differentiation process; Cell-Extracellular Matrix; Choline Chloride Dihydrogen Phosphate; Choline Phosphate; Choline Phosphate Chloride; Chromatin; Chromatin Structure; Clinical; Collagen; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); condensation; Cues; Data; Development; DIF; Differentiation and Growth; Differentiation Antigens; Differentiation Markers; Disease; disease/disorder; Disorder; ECM; Editorial Comment; Editorial Comment (PT); Elements; ELK-1; ELK1; ELK1 gene; end stage disease; Endothelial Cells; Environmental Factor; environmental risk; Environmental Risk Factor; Equilibrium; Ethanaminium, N, N, N-trimethyl-2-(phosphonooxy)-, chloride; experiment; experimental research; experimental study; Extracellular Matrix; Figs; Figs - dietary; GDCF-2; GDCF-2 HC11; Gel; Gene Down-Regulation; gene repression; Gene Transcription; Genes; Genetic Transcription; Goals; HC11; heavy metal lead; heavy metal Pb; histone modification; Hybrids; improved; In element; in vivo; Indium; inhibitor; inhibitor/antagonist; Injury; insight; Investigation; Laboratories; Lead; Leiomyocyte; Lesion; Ligand Binding Protein; macrophage; Marker Antigens; Markers, Differentation; Marrow monocyte; Matrix Metalloproteinases; MCAF; MCP-1; MCP1; Mediating; MGC9434; migration; Mitogens; MMPs; Molecular; Molecular Interaction; monocyte; MTGN; myocardin; Myocytes, Smooth Muscle; myosin heavy chain; Myosin Heavy Chains; Nature; new therapeutic target; novel; PAF receptors; Pathogenesis; Pattern; Pb element; PDGF; Phosphatides; Phosphocholine; Phospholipids; Phosphorylation; Phosphorylcholine; Phosphorylcholine Chloride; Physical condensation; platelet activating factor receptor; Platelet-Derived Growth Factor; Play; Pluronics; Principal Investigator; Process; Production; programs; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); protein blotting; Protein Phosphorylation; PTAFR protein; Published Comment; Receptor Signaling; Recommendation; Regulatory Element; RegulatoryElement; Reporter; research study; response; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; RNA Expression; RNA, Small Interfering; Role; RT-PCR; RTPCR; Rupture; screening; Screening procedure; screenings; SCYA2; Series; Signal Pathway; siRNA; Small Interfering RNA; SMC-CF; Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; social role; Staging; Streaks, Arterial Fatty; System; System, LOINC Axis 4; Testing; Thrombosis; Time; Tissue Inhibitor of Metalloproteinases; TNF; TNF A; TNF gene; TNFSF2; Transcription; Transcription Regulation; Transcription Repression; Transcription, Genetic; Transcriptional Control; Transcriptional Regulation; Transcriptional Repression; transgenic; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Gene; vascular; Viewpoint; Viewpoint (PT); vulnerable plaque; Western Blotting; Western Blottings; Western Immunoblotting; Yeasts
Project start date: 2008-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01HL087867-04 (2011): $378750
MEDICAL SCIENTIST TRAINING PROGRAM
K Gary, Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5T32GM007267-33 from National Institute Of General Medical Sciences
Abstract: The Medical Scientist Training Program (MSTP) at the University of Virginia prepares students for future careers in academic medicine. The goal of our Program is to provide students with the knowledge and skills to lead efforts to identify disease mechanisms, and to treat and cure human disease in the 21st Century. We have developed a highly integrated curriculum, as well as numerous MSTP policies and programmatic activities to optimize the development of trainees as physician scientists. From the onset, students take a combination of medical, graduate, and unique MSTP courses. These courses, combined with a highly flexible clerkship schedule, allow students to complete requirements for the M.D. and Ph.D. degrees in an efficient manner. The summer months in the first two years are devoted to completing research rotations. In year 03, students enter Graduate School in one of seven cross-departmental Biomedical Sciences Graduate Programs. After completing their Ph.D., students return to Medical School and complete 16 months of required clinical clerkships, as well as elective clerkships as desired. We have an active recruiting program that consists of a Summer Undergraduate Research Program, faculty visits to undergraduate campuses, and an early admissions program in the fall, in addition to standard admissions in the spring. We have over 150 primary mentors with whom students can conduct their thesis projects in a wide range of biomedical areas. All mentors have national level peer review funding and are recognized as leaders in their respective disciplines. We also have many clinician scientist role models in the program, and physician scientist co- mentors who serve to enhance the biomedical relevance/significance of dissertation projects. The program has a track record of its past graduates having highly successful careers as physician scientists at Universities, the NIH, in Industry, and the FDA, and many currently have their own independently funded laboratories. In summary, we feel that the unique training program that we have put in place, combined with our exceptional strengths in the basic and clinical sciences, provide an extremely strong environment for training physician scientists who will become leading academic investigators. RELEVANCE This training program is focused on preparing extraordinarily bright and talented men and women for a life- long career as physician scientists where they can pioneer major advances in our understanding and treatment of human disease. Upon completion of the Program, trainees are uniquely qualified to conduct high impact basic, translational and clinical research needed to develop exciting new diagnostic tests, preventative measures, and therapies for the major diseases that afflict mankind
Keywords: Medical; Scientist; Training Programs
Project start date: 1977-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5T32GM007267-33 (2011): $541068
INTERPLAY BETWEEN THE HOST MILIEU AND HUMAN NEURAL STEM CELLS IN STROKE REPAIR
K Gary, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 5R01NS058784-04 from National Institute Of Neurological Disorders And Stroke
Abstract: Stroke is the number one cause of disability among Americans each year. Currently there is no therapy to cure stroke patients except the thrombolytic treatments, which have limited use. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (hNPCs) as a potential therapy. We and others have shown that neural stem/progenitor in some cases can improve neurological function in rodents. However, transplant viability and functional outcome vary widely across studies. Our overall hypothesis is that hNPCs facilitate long-term functional by enhancing endogenous repair mechanisms through secretion of trophic factors. Including a focus on the trophic factors gives a mechanistic understanding of how transplanted stems cells augment endogenous repair processes. Importantly, we do not believe that the cells enhance recovery integrating into the host brain circuitry. In Specific Aim 1, we determine the effect of the transplanted cells on several endogenous repair mechanisms as well as the trophic factors expressed by the hNPCs in vivo over time, and then correlate these phenomena with functional recovery. We then test specific factors by manipulating their expression levels in hNPCs before transplantation. In Specific Aim 2, we determine the host microenvironment that is most conducive to cell-induced repair by varying the timing of transplantation post- stroke, with the goal of finding the optimal time to transplant. We also test the interplay between the host microenvironment and hNPCs by surveying host factors that are affected by hNPCs and also modifying the hNPCs´ sensitivity to signals for migration and survival from the host´s microenvironment. Together these aims will help identify the optimal time to transplant human neural progenitor cells after stroke and link successful cell therapy with critical molecular and cellular mechanisms that underlie endogenous repair after stroke. Graft survival and biology, and its effect on host repair mechanisms, will be assessed using immunohistochemistry. Functional recovery will be examined using behavioral tests. Our expertise in stroke research and cellular therapies (Kelly, 2004), neural stem cell biology and culture methods (Palmer, 2001), synaptogenesis (Christopherson, 2005), imaging (Micheva, 2007) and genetic manipulation of hNPCs (Suzuki, 2007) provide an excellent opportunity to develop a cross-disciplinary effort to study cell transplants for brain injury at Stanford. Stroke is the number one cause of disability among Americans each year, and there are limited therapeutic treatments that can be offered. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (NPCs) as a potential therapy. In this proposal we seek to understand how the NPCs augment the brain´s natural repair processes after stroke so that we can enhance these properties in the future
Keywords: Address; Adult; Affect; American; angiogenesis; Animal Model; Apoptotic; axonal sprouting; base; behavior test; Behavioral; Biological Assay; Biological Models; Biology; Blood Cells; Bone Marrow Cells; Brain; Brain Injuries; Cell Culture Techniques; Cell Line; Cell physiology; Cell Therapy; Cell Transplantation; Cell Transplants; cell type; Cells; Cerebral Ischemia; Cessation of life; chemokine; Clinic; Clinical; Clinical Trials; Communication; Confocal Microscopy; Deoxyuridine; disability; Disease; Embryo; Event; experience; FDA approved; functional outcomes; Future; genetic manipulation; Goals; Golgi Apparatus; Graft Survival; Health; Human; Huntington Disease; Image; Imaging Techniques; immortalized cell; Immunohistochemistry; improved; in vivo; indexing; infancy; Infarction; Inflammatory; Inflammatory Response; Integration Host Factors; Ischemia; kidney cell; Knowledge; Label; Lesion; Link; Location; Lysosomal Storage Diseases; Measures; Methods; migration; Modeling; Molecular; molecular imaging; Molecular Probes; Monitor; Motor; Mus; neovascularization; nerve stem cell; nervous system disorder; Nervous System Physiology; Neuroepithelial Cells; neurogenesis; neuron loss; Neurons; Outcome; overexpression; Parkinson Disease; Patient observation; Patients; post stroke; Principal Investigator; Process; progenitor; programs; Property; Rattus; Recovery; Recovery of Function; relating to nervous system; Relative (related person); repaired; Research; Research Personnel; research study; Resolution; Rodent; Rodent Model; Role; Signal Transduction; Spielmeyer-Vogt Disease; Spinal cord injury; Staining method; Stains; stem; stem cell biology; Stem cell transplant; Stem cells; stroke; stroke recovery; stroke therapy; Stromal Cell-Derived Factor 1; success; Surveys; synaptogenesis; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; tomography; tool; Transplantation; Umbilical Cord Blood; Vascular Endothelial Growth Factors; Work
Project start date: 2008-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAS-07-189
5R01NS058784-04 (2011): $421669
DEVELOPING NEW STRATEGIES FOR TARGETING MTOR AND IGF-1R/PI3K/AKT PATHWAYS IN SARC
K Gary, Chief, Melanoma And Sarcoma Service
Sloan-kettering Institute For Cancer Rescity: New York country: United States (us)
Grant 4R01CA140331-03 from National Cancer Institute
Abstract: Sarcoma is a heterogeneous disease with at least 50 different subtypes. This genetic diversity makes the development of new targeted therapies particularly challenging. However, one consistent theme now emerging is that activation of the IGF-1R/PI3K/Akt and mTOR pathways are critical for sarcoma tumor oncogenesis, proliferation, and survival across histologic subtypes. Despite the compelling rationale to target mTOR in sarcomas, results from clinical studies examining the efficacy of rapamycin analogues ("rapalogues") have been disappointing. Several studies to date have suggested that persistent or increased Akt activation in the context of mTOR inhibitors may represent a mechanism of resistance to this class of therapies. Our own data in a panel of sarcoma cell lines confirms that rapamycin induces increased Akt phosphorylation. We hypothesize that persistent or increased Akt activation is a critical mechanism of clinical sarcoma resistance to mTOR inhibition with rapamycin analogues and that future therapeutic strategies must be focused upon combined mTOR and Akt inhibition. Towards this end, we have identified two classes of sarcoma cell lines 1) "IGF-1R dependent" cells for which combined IGF-1R and mTOR targeting results in decreased p-Akt levels and hence enhanced anti-proliferative effects; and 2) "IGF-1R independent" cells for which IGF-1R inhibition fails to decrease p-Akt levels or enhance anti-tumor effects. These classifications not only will provide the framework by which to clinically evaluate mTOR targeting agents in clinical trials, but also highlight differences in sarcoma biology that suggest novel strategies for overcoming Akt mediated resistance. Additionally, we have identified a high rate of PIK3CA mutations in myxoid-round cell liposarcomas and observed that different classes of PIK3CA mutations correspond to dramatically different levels of Akt activation in patient tumor samples. In order to advance our understanding of how to manipulate these pathways for sarcoma therapy, the specific aims of this project are to 1) conduct clinical trials in sarcoma with combinations of TORC1 and IGF-1R inhibitors, as well as a first-in-class TORC1/2 inhibitor; 2) evaluate strategies for reducing activated Akt in the context of TORC1 inhibition in IGF-1R -dependent and -independent sarcoma cells; and 3) study the impact of PIK3CA mutations upon myxoid-round cell liposarcoma biology and the susceptibility of these tumors to mTOR targeting. Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (mTOR and IGF- 1R/PI3K/Akt) should result in major advances in the treatment and cure of this disease
Keywords: Biology; CCI-779; Cell Line; Cells; chemotherapy; Classification; Clinical; clinical efficacy; Clinical Research; Clinical Trials; Complex; Conduct Clinical Trials; Critical Pathways; Data; Development; Disease; effective therapy; Future; Gene Mutation; Generations; Growth; Health; Histologic; In Vitro; in vivo; inhibitor/antagonist; Malignant Neoplasms; Mediating; mTOR protein; Multiprotein Complexes; Mutation; Myxoid/Round Cell Liposarcoma; novel strategies; Nutrient; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; PIK3CA gene; Predisposition; Publishing; Reporting; Resistance; resistance mechanism; response; Sampling; sarcoma; Signaling Molecule; Sirolimus; success; Therapeutic; tumor; tumor growth; tumorigenesis; Variation (Genetics)
Relevance: Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (mTOR and IGF- 1R/PI3K/Akt) should result in major advances in the treatment and cure of this disease
Project start date: 2009-07-16
Project end date: 2013-06-30
Budget start date: 1-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
4R01CA140331-03 (2011): $728428
P2 - DEVELOPING NEW STRATEGIES FOR TARGETING PDGFR/PI3K/AKT PATHWAYS IN SARCOMA
K Gary, Chief, Melanoma And Sarcoma Service
Sloan-kettering Institute For Cancer Rescity: New York country: United States (us)
Abstract: Sarcoma is a heterogeneous disease with at least 50 different subtypes. Given this genetic diversity, the developnnent of new targeted therapies is particularly challenging. However, one consistent theme now emerging is that receptor tyrosine kinase (RTK) activation of PI3K/Akt and mTOR pathways are critical for sarcoma tumor oncogenesis, proliferation, and survival across histologic subtypes. Despite the compelling rationale to target RTKs and mTOR in sarcomas, results from clinical studies have been disappointing. Hence, a new direction in drug development is needed to optimize therapeutic approaches directed at these rational targets. We hypothesize that PDGFRA represents a critical therapeutic target in a subset of sarcomas that can be effectively targeted in combination with mTOR inhibitors and chemotherapy. Our specific aims are to 1) conduct a phase Ib/ll clinical trial of imatinib and everolimus in PDGFRA expressing synovial sarcomas; 2) conduct a phase Ib/ll randomized clinical trial of doxorubicin with or without IMC-3G3, a human monoclonal antibody specific for PDGFRA; and 3) investigate anti-tumor mechanisms of PDGFRA inhibition in sarcoma tumors. Public Health Statement Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (PDGFRA and mTOR) should result in major advances in the treatment and cure of this disease. Sloan-
Keywords: CCI-779; cell growth; chemotherapy; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Complex; Critical Pathways; Data; Dependency (Psychology); Development; Disease; Doxorubicin; drug development; Drug resistance; effective therapy; Ewings sarcoma; Generations; Growth Factor; Histologic; human monoclonal antibodies; Imatinib; In Vitro; inhibitor/antagonist; Malignant Neoplasms; Mediating; mTOR protein; Multiprotein Complexes; neoplastic cell; Nutrient; Pathologic; Pathway interactions; Patients; PDGFRA gene; PDGFRB gene; Pharmaceutical Preparations; Phase; PI3K/AKT; Predisposition; programs; public health medicine (field); Publishing; Randomized Clinical Trials; Receptor Protein-Tyrosine Kinases; Reporting; response; sarcoma; SDZ RAD; Signal Pathway; Signal Transduction Pathway; Signaling Molecule; Sirolimus; soft tissue; synovial sarcoma; Therapeutic; therapeutic target; tumor; tumor growth; tumorigenesis; Tyrosine Kinase Inhibitor; Variation (Genetics); Xenograft procedure
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50CA140146-02_8365 (2011): $218417
STANFORD NEUROSURGERY RESIDENT RESEARCH EDUCATION PROGRAM
K Gary
Stanford Universitycity: Stanford country: United States (us)
Grant 3R25NS065741-03S1 from National Institute Of Neurological Disorders And Stroke
Abstract: Project The purpose of this Stanford Neurosurgery Resident Research Education Program is to provide education in basic and clinical research to neurosurgery residents with the goal of fostering their growth into clinician scientists. Its goal is to educate and train neurosurgeons capable of establishing and directing a scientific laboratory throughout their careers. The strategy is to identify residents with the potential for scientific research and place them for a two year term in the laboratories of senior, highly experienced research scientists. They will also receive extensive counseling by the neurosurgical directors of the program and participate in seminars on research skills and ethical research behavior. Their progress and the success of the overall program will be repeatedly assessed and appropriate changes in the program will be made. It is hoped that this program will produce neurosurgeons capable of making new discoveries regarding the causes of diseases of the brain and spinal cord, that new, more effective treatments will result, and, in fulfillment of the mission of the NIH, that the health of persons afflicted with these diseases will be improved. This project seeks support for the education of neurosurgical residents in research. It is hoped that this will produce neurosurgeons capable on making new discoveries regarding the causes of diseases of the brain and spinal cord and that new, more effective treatments will result
Keywords: Basic Research; Basic Science; Behavior; Brain Diseases; Brain Disorders; career; career development; Clinical Research; Clinical Study; Counseling; Disease; disease/disorder; Disorder; Education; Educational aspects; effective therapy; Encephalon Diseases; Ethics; experience; Fostering; Funding; Generalized Growth; Goals; Growth; Health; improved; Intracranial Central Nervous System Disorders; Intracranial CNS Disorders; Investigation; Laboratories; Medulla Spinalis; Mission; National Institutes of Health; National Institutes of Health (U.S.); Neurologic; Neurological; Neurosurgeon; neurosurgery; NIH; ontogeny; Persons; programs; Programs (PT); Programs [Publication Type]; public health relevance; Research; Science of neurosurgery; Scientist; skills; Spinal Cord; success; surgeon, neuro-; Tissue Growth; Training; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; United States National Institutes of Health
Relevance: This project seeks support for the education of neurosurgical residents in research. It is hoped that this will produce neurosurgeons capable on making new discoveries regarding the causes of diseases of the brain and spinal cord and that new, more effective treatments will result
Project start date: 2009-03-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: RFA-NS-09-001
3R25NS065741-03S1 (2011): $71119
EPIGENETIC CONTROL OF SMOOTH MUSCLE CELL LINEAGE AND PHENOTYPIC SWITCHING
K Gary, Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5R01HL057353-14 from National Heart, Lung, And Blood Institute
Abstract: Altered control of the differentiated state of the smooth muscle cell (SMC) or "phenotypic switching" is known to play a critical role in the development and/or progression of a number of major human diseases including atherosclerosis, asthma, and post-angioplasty restenosis. However, the mechanisms that control SMC phenotypic switching are poorly understood. The focus of this proposal is to determine mechanisms by which histone patterning of chromatin, a key epigenetic control in higher eukaryotic cells, regulates SMC differentiation in development and disease. Of major significance, during the current funding period, we completed a series of pioneering studies showing that development of SMC from embryonic stem cells (ESC) is associated with acquisition of a unique pattern of histone modifications at SMC marker gene loci that distinguish them from non-SMC, and make these loci permissive for transcriptional activation. In contrast, phenotypic switching of SMC in response to vascular injury, or PDGF BB treatment, was associated with loss of many of these SMC-selective histone modifications, as well as acquisition of histone changes associated with transcriptional silencing/chromatin condensation. However, H3K4 demethylation at SMC marker gene loci, a histone change that appears during development of SMC from ESC, was completely unchanged in all models of SMC phenotypic switching examined, suggesting that it may be relatively "fixed", and serve to preserve SMC "lineage memory" during reversible phenotypic switching. Taken together, results indicate that there is a distinct pattern of histone modifications that distinguishes SMC from non-SMC, and that these SMC- and gene locus-specific epigenetic modifications are likely to play a key role in regulating SMC differentiation marker gene expression in development and disease. The focus of this project is to test the hypothesis that development of SMC from embryonic stem cells is associated with acquisition of a unique pattern of histone modifications at SMC marker (and regulatory) gene loci and that these histone modifications play a key role in determining the permissiveness of these gene loci for transcriptional activation as well as in providing "SMC lineage memory" during reversible phenotypic switching. We will address this hypothesis by addressing the following two specific aims. Aim 1 is to determine mechanisms by which SMC selective/specific chromatin modifications regulate expression of SMC differentiation marker and regulatory genes during development of SMC lineages from multipotential stem cells. This will include the first studies to directly test the role of specific histone modifications in control of SMC lineage/differentiation, and how these histone modifications are acquired during development. Aim 2 is to define the role of epigenetic modifications in mediating reversible phenotypic switching of vascular SMC in response to vascular injury in vivo or treatment of cultured SMC with PDGF BB. Studies will define fundamental mechanisms that control differentiation of SMC, and are likely to lead to novel therapies for treatment of diseases in which SMC phenotypic switching plays a major role
Keywords: Acetylation; Actins; Address; adult stem cell; Angioplasty; Arterial Fatty Streak; Asthma; atherogenesis; Atherosclerosis; base; Binding (Molecular Function); Biological Assay; Biological Models; Blood Vessels; Boxing; CEBPE gene; Cell Differentiation process; Cell Lineage; cell type; Cells; Chimeric Proteins; Chromatin; chromatin immunoprecipitation; chromatin modification; Complex; CREB-binding protein; Cues; Cultured Cells; demethylation; Development; Differentiation and Growth; Differentiation Antigens; Disease; DNA Sequence; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Elements; Embryo; embryonic stem cell; Endothelial Cells; Enhancers; Environmental Risk Factor; Enzymes; EP300 gene; Epigenetic Process; Equilibrium; Eukaryotic Cell; Evolution; Excision; Exhibits; Extracellular Matrix; factor A; Fibroblasts; Figs - dietary; Funding; G9a histone methyltransferase; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; HDAC2 gene; histone acetyltransferase; Histone Deacetylation; Histone H4; histone methyltransferase; histone modification; Histones; human CREBBP protein; human disease; Immunoprecipitation; In Vitro; in vivo; Indium; Inherited; Injury; interest; Laboratories; LacZ Genes; Lead; Lesion; macrophage; Mammalian Cell; Matrix Metalloproteinases; mature animal; Mediating; Memory; Methylation; migration; Modeling; Modification; Molecular; mutant; myocardin; Nature; novel; Nuclear Extract; nuclease; Pathogenesis; Pattern; Peptides; permissiveness; Physical condensation; Platelet-Derived Growth Factor; platelet-derived growth factor BB; Play; Process; Production; programs; Promoter Regions (Genetics); Promotor (Genetics); Rattus; Regulation; Regulator Genes; Regulatory Element; Repression; response; restenosis; Reverse Transcriptase Polymerase Chain Reaction; Role; selective expression; Series; Small Interfering RNA; Smooth Muscle Myocytes; Staging; Stem cells; System; Testing; Time; Tissue Inhibitor of Metalloproteinases; Transcription Coactivator; transcription factor; Transcriptional Activation; Transgenes; Transgenic Mice; Transgenic Organisms; Vascular Diseases
Project start date: 1998-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01HL057353-14 (2011): $377573