PREP AND PROTECTIVE IMMUNE RESPONSES AGAINST HIV-1
M Jennifer
University Of Washingtoncity: Seattle country: United States (us)
Grant 1R01AI096968-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Pre-exposure prophylaxis (PrEP), in which HIV-1 uninfected persons use oral or topical antiretrovirals to protect against sexual HIV-1 acquisition, is one of the most promising new HIV-1 prevention strategies. It has been hypothesized that PrEP, by aborting infections through direct anti-viral activity, may allow HIV-1 specific immune responses to develop in exposed persons. In non-human primate models, T cell responses in blood recognizing SHIV antigens were achieved half of animals receiving PrEP. A "chemotherapeutic" effect of PrEP could enhance PrEP´s efficacy for preventing HIV-1 acquisition, blunt early HIV-1 replication for PrEP breakthrough infections, improve immunogenicity and efficacy of a partially-effective HIV-1 vaccine, and provide anti-HIV-1 protection after PrEP is discontinued. PrEP clinical trials provide a unique opportunity to characterize anti-HIV-1 immune responses in persons on PrEP (compared directly to those on placebo), explore mechanisms for PrEP protection, and anticipate PrEP as "chemovaccination" paired with candidate HIV-1 vaccines. We are conducting the largest phase III efficacy trial of PrEP - the Partners PrEP Study, a randomized, double-blind, placebo-controlled, clinical trial of oral tenofovir and emtricitabine/tenofovir PrEP among HIV-1 uninfected partners in 4758 African HIV-1 serodiscordant couples. In July 2011, we demonstrated in the Partners PrEP Study that daily oral PrEP using tenofovir and emtricitabine/tenofovir significantly reduced HIV-1 acquisition risk, by 62% (p=0.0003) and 73% (p<0.0001) respectively. We propose to explore anti-HIV-1 responses in HIV-1 exposed but uninfected persons receiving PrEP, evaluate the relationship between anti-HIV-1 immune responses and protection against HIV-1 acquisition and control of viral replication in breakthrough infections observed during prospective follow-up, and, in an exploratory study, collect and test mucosal samples from persons on PrEP to evaluate immune responses at the site of HIV-1 exposure. Our proposed project is innovative in its use of a randomized, placebo-controlled clinical trial population, allowing unbiased, longitudinal comparisons of the effect of PrEP (versus placebo) on induction of HIV-1-specific immune responses, in the study population of HIV-1 serodiscordant couples, allowing precise definition of the degree of HIV-1 exposure, and in its application of state-of-the-art immunologic assays to study the impact of PrEP on HIV-1 protection and control of viral replication. We will 1) determine the frequency, magnitude, and persistence of anti-HIV-1 innate and adaptive immune responses in persons receiving PrEP compared to placebo, 2) assess the effect of anti- HIV-1 responses on protection against HIV-1 acquisition (controlling for PrEP randomization arm) and control of HIV-1 replication (in those with breakthrough infections in spite of PrEP), and 3) measure anti-HIV- 1 innate and adaptive immune responses in mucosal biopsy samples from HIV-1 uninfected persons on PrEP compared to placebo. Our testing will focus on peripheral blood T cell responses, as these have been found most frequently as a potential correlate of HIV-1 resistance in highly-exposed HIV-1 seronegative persons, and we will also test for peripheral innate immune responses (NK cell phenotyping and functional studies, dendritic cell phenotyping). In mucosal samples, we will test for both adaptive and innate immune responses. Our hypothesis is that PrEP allows for development of host immunity that will provide protection against HIV-1 infection and disease. We have assembled a multinational team with the multidisciplinary HIV-1 expertise necessary to execute the proposed studies. Our findings will be directly relevant to the development of a prophylactic HIV-1 vaccine or a combined PrEP-vaccine strategy that might offer greater protection against HIV-1 than either intervention alone. Pre-exposure prophylaxis (PrEP), in which HIV-1 uninfected persons use oral or topical antiretroviral medications to protect against sexual HIV-1 acquisition, is a powerful new HIV-1 prevention strategy. By blocking HIV-1 through direct anti-viral activity, PrEP may allow HIV-1 specific immune responses to develop in exposed persons - acting like a "chemotherapeutic" vaccine. These immune responses may enhance the protective effects of PrEP against HIV-1 infection, help control HIV-1 infection in persons who acquire HIV-1 in spite of PrEP, and enhance the effects of a partially-effective HIV-1 vaccine. We propose to explore anti-HIV-1 immune responses in HIV-1 exposed by uninfected persons participating in the largest clinical trial of PrEP
Keywords: African; Animals; Anti-Retroviral Agents; Antigens; Antiviral Agents; arm; Biopsy Specimen; Blood; CD4 Lymphocyte Count; Clinical Trials; Controlled Clinical Trials; Couples; Dendritic Cells; Development; Disease; Dose; Double-Blind Method; efficacy trial; emtricitabine; Exposure to; follow-up; Frequencies (time pattern); Future; Genital system; Heterosexuals; HIV-1; Immune response; Immunity; immunogenicity; Immunologics; Immunology procedure; improved; Individual; Infant; Infection; innovation; Intervention; Measures; Modeling; Mucous Membrane; multidisciplinary; Natural Killer Cells; Nested Case-Control Study; nonhuman primate; Oral; Participant; Peripheral; peripheral blood; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Plasma; Population; Population Study; preclinical study; prevent; Prevention strategy; prophylactic; Prophylactic treatment; prospective; protective effect; Randomized; Resistance; response; Risk; Sampling; sex; Sexual Partners; Signal Transduction; simian human immunodeficiency virus; Site; Source; Surface; T cell response; Tenofovir; Testing; Time; Tissue Sample; Unsafe Sex; Vaccines; Viral; Viral Physiology; Woman
Relevance: Pre-exposure prophylaxis (PrEP), in which HIV-1 uninfected persons use oral or topical antiretroviral medications to protect against sexual HIV-1 acquisition, is a powerful new HIV-1 prevention strategy. By blocking HIV-1 through direct anti-viral activity, PrEP may allow HIV-1 specific immune responses to develop in exposed persons - acting like a "chemotherapeutic" vaccine. These immune responses may enhance the protective effects of PrEP against HIV-1 infection, help control HIV-1 infection in persons who acquire HIV-1 in spite of PrEP, and enhance the effects of a partially-effective HIV-1 vaccine. We propose to explore anti-HIV-1 immune responses in HIV-1 exposed by uninfected persons participating in the largest clinical trial of PrEP
Project start date: 2012-04-01
Project end date: 2016-03-31
Budget start date: 1-APR-2012
Budget end date: 31-MAR-2013
1R01AI096968-01A1 (2012): $761717
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to M Jennifer
VISUAL SIGNALS IN AUDITORY MIDBRAIN
M Jennifer, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01EY016478-06 from National Eye Institute
Abstract: What we see helps us interpret what we hear. Integrating visual and auditory information is a fundamental aspect of human behavior. Impairments in visual-auditory integration impact numerous aspects of human health, ranging from communication and language to attention and movements in a complicated environment. However, the neural basis of this ability is not well understood. Previous work in barn owls has focused on how the visual information is used to calibrate the representation of auditory space, and has implicated the inferior colliculus in this process. However, little is known about this area in primates. Rhesus monkeys have visual and auditory systems that are quite similar to humans, and serve as an excellent animal model for studying the neural mechanisms underlying visual-auditory integration. Visual-auditory integration in humans and monkeys is different from barn owls because primates can move their eyes whereas barn owls cannot. Thus, primate visual auditory integration requires three signals visual, auditory, and eye position signals. It has long been known that the primate IC contains auditory information, and we have recently shown that it contains eye position information (Groh et al., Neuron, 2001). Here, we turn to visual information in this structure. We have recently discovered robust visual responses in the IC of awake monkeys. In this proposal, we seek to study the properties of these visual responses and how they relate to auditory and eye position information in this brain region. Specifically, we aim to (1) characterize the visual response properties (Aim 1), (2) determine the frame of reference of these visual responses (Aim 2), and determine how IC neurons respond to combined visual and auditory stimuli, especially when a spatial disparity between these stimuli produces a ventriloquism affect/aftereffect (Aim 3). The mechanisms of visual influence over auditory processing investigated here bear on a variety of disorders involving both visual and auditory components, such as dyslexia and autism. These experiments will yield a greater understanding of subcortical mechanisms for visual-auditory integration within the auditory pathway and may ultimately lead to treatment regimens to help ameliorate the deficits experienced by patients with these disorders
Keywords: Acoustic; Acoustics; Affect; Animal Behavior; Animal Model; Animal Models and Related Studies; Anterior Quadrigeminal Body; Aotinae; Area; Attention; Auditory; auditory pathway; Auditory pathway structure; Auditory Pathways; auditory stimulus; Auditory system; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; awake; Barn Owls; base; Bears; Behavior; Binding; Binding (Molecular Function); biological signal transduction; body movement; Brain region; Cell Communication and Signaling; Cell Signaling; Communication; Corpora quadrigemina, superior colliculus; Disease; disease/disorder; Disorder; Dissociation; Douroucouli; Dyslexia; Elements; Environment; experience; experiment; experimental research; experimental study; Eye; Eyeball; Grant; Head; Health; Hearing; hearing perception; heavy metal lead; heavy metal Pb; Human; Human, General; Illusions; Impairment; Inferior Colliculus; interest; Intracellular Communication and Signaling; Investigators; Kanner`s Syndrome; Language; Lead; Light; Location; Macaca mulatta; Mammals, Primates; Man (Taxonomy); Man, Modern; Maps; Mediating; Mesencephalon; Mid-brain; Midbrain; Midbrain structure; model organism; Molecular Interaction; Monitor; Monkeys; Movement; multisensory; Nerve Cells; Nerve Unit; Nervous; neural; Neural Cell; neural mechanism; Neurocyte; neuromechanism; neuronal; Neurons; Night Monkey; Optic Tectum; Outcome; owl monkey; pathway; Pathway interactions; Patients; Pb element; Perception; Photoradiation; Position; Positioning Attribute; Posterior Quadrigeminal Body; Prevalence; Primates; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protocols, Treatment; Pursuit, Saccadic; receptive field; Regimen; relating to nervous system; Research Personnel; research study; Researchers; response; RGM; Rhesus; Rhesus Macaque; Rhesus Monkey; Saccades; Saccadic Eye Movements; Shapes; Signal Transduction; Signal Transduction Systems; Signaling; sound; Sound; Sound - physical agent; sound perception; Source; Stimulus; Structure; Superior Colliculus; superior colliculus Corpora quadrigemina; Tectums, Optic; Treatment Protocols; Treatment Regimen; Treatment Schedule; Ursidae; Ursidae Family; Visual; visual information; visual receptive field; visual stimulus; Visual System; Visual system structure; visual tectum; Wood; Wood material; Word Blindness; Work
Project start date: 2006-01-01
Project end date: 2011-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2011
5R01EY016478-06 (2010): $345545
GASTRIC CANCER PREVENTION: EVALUATING U.S. RISK FACTOR TRENDS AND NEW TECHNOLOGY
M Jennifer, Research Fellow
Harvard University (sch Of Public Hlth)city: Boston country: United States (us)
Grant 5K07CA143044-02 from National Cancer Institute
Abstract: The goal of the proposed research is to identify effective gastric cancer prevention programs that improve cancer outcomes, reduce disparities, and enhance the cost-effectiveness of gastric cancer prevention in the U.S. This will be accomplished by constructing a flexible decision-analytic simulation model of gastric cancer capable of estimating the contribution of risk factor patterns on gastric cancer trends and assessing the costs, benefits, and cost-effectiveness of primary (smoking cessation) and secondary (surveillance) prevention strategies. As several factors are changing the landscape of gastric cancer control, including a better understanding of the disease natural history, role of risk factors on disease progression, and new noninvasive endoscopic technology to detect and treat precancerous and cancerous lesions, this model will synthesize available clinical, epidemiologic, and economic data to project long-term outcomes and guide clinical study design. Our specific aims are (1) to develop a natural history model of gastric cancer, including the role of risk factors on disease progression. This model will be empirically calibrated using U.S. epidemiologic data on age-specific prevalence and incidence of precancerous lesions and cancer; (2) to estimate the decline in gastric cancer incidence attributable to declining prevalence of H. pylori, smoking, and other risk factors. Using a population-based model of gastric cancer we will incorporate data on risk factor trends to forecast gastric cancer incidence and mortality; (3) to assess the cost-effectiveness of technology-based surveillance and treatment strategies for patients with precancerous lesions. We will evaluate the effectiveness of endoscopic and serology-based diagnostic and therapeutic technologies for dysplastic and asymptomatic cancerous lesions; (4) to compare the relative effectiveness of alternative gastric cancer control strategies on disparities. We will develop natural history models for specific race/ethnicity, immigrant, and other select subgroups, incorporate demographic trends, and assess the impact of prevention and treatment strategies to improve cancer outcomes and reduce disparities. In summary, this research will synthesize the best available data, improve upon an existing modeling framework, and develop a new set of analytic tools to estimate and project gastric cancer trends; establish management guidelines for patients with gastric precancerous lesions; and provide insight on the relative costs, benefits, and risks associated with different gastric cancer prevention and control strategies. My career goal is to become an independent investigator dedicated to the application of multidisciplinary, decision- analytic methods to improve cancer prevention and control policies. In conjunction with additional training in secondary data analysis, advanced decision-analytic methods, and epidemiology, the execution of this proposed mentored research in a multidisciplinary and highly-collaborative environment will provide the additional experience, knowledge, and skills needed to successfully transition to research independence
Keywords: Age; American; base; Benefits and Risks; biomarker; Cancer Control; Cancer Etiology; cancer health disparity; cancer prevention; Cancerous; career; Cessation of life; Clinical; Clinical Research; Cohort Studies; cost effectiveness; Costs and Benefits; Cross-Sectional Studies; Data; Data Analyses; Databases; Diagnostic; Disease; disease natural history; Disease Progression; Early Diagnosis; Early treatment; Economics; effective intervention; Effectiveness; Environment; epidemiologic data; Epidemiologic Methods; Epidemiology; Ethics; Ethnicity aspects; Exercise; experience; falls; flexibility; Future; gastric cancer prevention; Gastric Intestinal Type Adenocarcinoma; Goals; Guidelines; Helicobacter pylori; high risk; Immigrant; improved; Incidence; Individual; insight; Intervention; Knowledge; Lesion; Life Expectancy; Malignant Neoplasms; malignant stomach neoplasm; mathematical model; Measures; Medical Surveillance; Mentors; Methodology; Methods; Modeling; models and simulation; modifiable risk; Mortality Vital Statistics; multidisciplinary; Natural History; new technology; NHANES; novel diagnostics; novel therapeutics; Outcome; Output; Patients; Pattern; Policies; Population; population based; Premalignant; Prevalence; prevent; Prevention; Prevention program; Prevention strategy; Publishing; Race; Recommendation; Relative (related person); Research; Research Design; Research Personnel; Risk Factors; Role; Science; Screening procedure; SEER Program; Serologic tests; skills; Smoking; smoking cessation; smoking prevalence; Societies; Stomach; Subgroup; surveillance data; surveillance strategy; Surveys; Techniques; Technology; Therapeutic; Time; tool; Training; treatment strategy; trend; Validation
Relevance: This project evaluates gastric cancer prevention strategies in the U.S., including targeted risk factor interventions and new endoscopic techniques for early detection and treatment of precancerous lesions. The objective is to improve cancer outcomes, reduce disparities, and enhance the cost-effectiveness of gastric cancer prevention in the U.S
Project start date: 2010-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-09-078
5K07CA143044-02 (2011): $150520
REGULATORY T CELL MODULATION OF IMMUNITY TO MUCOSAL VIRAL INFECTIONS
M Jennifer, Assistant Member
Fred Hutchinson Cancer Research Centercity: Seattle country: United States (us)
Grant 5R01AI087657-02 from National Institute Of Allergy And Infectious Diseases
Abstract: Regulatory T cells are well known for their role in dampening the immune responses to self-antigens and thereby helping to prevent autoimmune disease. Additionally, recent work has highlighted the importance of regulatory T cells in immunity to infectious disease. Thus, the question arises as to how regulatory T cells can participate in both of these goals so important to human survival - preventing damaging immune responses to self while simultaneously permitting immune responses to be generated to fight foreign infectious agents. Previous studies have pointed to a role for regulatory T cells in limiting late immune responses to various infectious agents, thereby minimizing immune response-induced tissue damage while preventing or diminishing pathogen clearance. However, we recently demonstrated a novel and unexpected role for regulatory T cells in facilitating early immune responses to genital herpes simplex-2 (HSV-2) infection by orchestrating a timely trafficking of immune effector cells to the site of infection where they can fight infection. Therefore, this unexpected finding of an immune response-promoting function of regulatory T cells has subsequently led to several new lines of work that will be addressed in this proposal. Specifically, we will first address the role of regulatory T cells during the immune response to primary challenge with genital HSV-2 infection and compare this role to that during a second common mucosal infection that is considered to be a major public health threat- influenza virus infection. We hypothesize that the role of Tregs can vary depending on the type of pathogen, the location of the cells, the timing of infection, and the route of infection, and so we expect that these two viral systems will provide a unique opportunity to compare and contrast the role of Tregs during different types of infections that infect different mucosal surfaces. Secondly, following up on work from our previous studies, we will characterize the mechanisms by which regulatory T cells modulate dendritic cell function during mucosal viral infections. Finally, we will determine if regulatory T cells must be antigen-specific in order to respond to genital HSV-2 infection. Results from these studies will help to reveal the roles of regulatory T cells during various types of mucosal viral infections at different mucosal surfaces of the body, as well as the different roles that regulatory T cells could play at various phases of the immune response to viruses. We expect that knowledge gained from this research program will assist in the generation of improved clinical interventions for mucosal viral infections, including vaccines. Our previously published work as well as preliminary data presented in this proposal suggests that regulatory T cells play several important roles in the immune response to viruses; thus, gaining an understanding of exactly what these cells do as well as where and when in the course of an immune response is vital for designing future vaccines that will allow regulatory T cells to effectively assist in generating and maintaining protective immune responses. Mucosal viral infections such as herpes and influenza pose a public health threat in the United States and worldwide. A role for regulatory T cells, which are potent negative regulators of the adaptive and innate immune responses, is poorly understood in the case of viral infection in general and in the cases of mucosal infections in particular. As mucosal exposure is the route via which the general population encounters the majority of common viruses that impact public health, the goal of this proposed research program is to better understand how regulatory T cells modulate immunity to mucosal viral infections. The proposed studies will assist in understanding the role that regulatory T cells play in HSV and influenza viral infections and disease progression, an important step in advancing the overall goal of finding new therapeutic targets for vaccines and treatments to combat mucosal viral infections
Keywords: Ablation; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Antibodies; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Models; Body Surface; Cell physiology; Cells; chemokine; Clinical; combat; Communicable Diseases; cytokine; Data; Dendritic Cells; design; diphtheria toxin receptor; Disease Progression; Down-Regulation; Effector Cell; Experimental Models; Exposure to; Failure (biologic function); fighting; Future; General Population; Generations; genital herpes; Goals; Herpesviridae; Human; human disease; Human Herpesvirus 2; IL2RA gene; Immune; Immune response; Immunity; improved; Infection; Infectious Agent; Inflammatory; Influenza; influenzavirus; Interferons; Intervention; Knock-in Mouse; Knowledge; Location; Lymphoid; Maintenance; Mediating; Memory; migration; mouse model; mucosal site; Mucous Membrane; Mus; new therapeutic target; novel; Organ; pathogen; Pathology; Peripheral; Phase; Play; prevent; Production; programs; public health medicine (field); public health relevance; Publishing; Regulatory T-Lymphocyte; Research; Resistance; response; Role; Route; Signal Transduction; Simplexvirus; Site; Specificity; Staging; Surface; System; T-Lymphocyte; Testing; Time; Tissues; trafficking; transcription factor; Transgenes; United States; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Work
Relevance: Mucosal viral infections such as herpes and influenza pose a public health threat in the United States and worldwide. A role for regulatory T cells, which are potent negative regulators of the adaptive and innate immune responses, is poorly understood in the case of viral infection in general and in the cases of mucosal infections in particular. As mucosal exposure is the route via which the general population encounters the majority of common viruses that impact public health, the goal of this proposed research program is to better understand how regulatory T cells modulate immunity to mucosal viral infections. The proposed studies will assist in understanding the role that regulatory T cells play in HSV and influenza viral infections and disease progression, an important step in advancing the overall goal of finding new therapeutic targets for vaccines and treatments to combat mucosal viral infections
Project start date: 2010-06-01
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01AI087657-02 (2011): $435600
THE ROSETTA ENZYME REDESIGN: TARGETING PON1 AS OP SCAVENGER
M Jennifer, Senior Fellow
University Of Washingtoncity: Seattle country: United States (us)
Grant 5K01ES018854-02 from National Institute Of Environmental Health Sciences
Abstract: Many organophosphate (OP) compounds are potent cholinesterase inhibitors and have extensively been used as pesticides and insecticides in agriculture, as a flame retardant in plastics and rubbers, and even as a gasoline additive [1-3]. Each year, there are approximately three million pesticide poisonings world-wide resulting in more than 200,000 deaths [1]. Long term exposures to these OP compounds in commercial products have been linked to several adverse health effects and permanent damages to our ecosystem. The search for enzymes that act as bioscavengers against toxic OP compounds has become an intense research topic. In this context, human serum paraoxonase, PON1 could become a promising scavenger against highly toxic OP compounds because 1) it is in human serum, 2) it can hydrolyze OP compounds, and 3) it displays large pH optima and performs optimally at physiological temperature [5-7]. However, PON1´s physiological role has not yet been unambiguously identified. It is considered to be a promiscuous enzyme [6]. In addition, PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme [5]. The proposed research is to re-engineer PON1 using a new approach that integrates both conformational dynamics and evolution information by 1) characterizing its catalytic activities, 2) identifying conformational diversities of the enzyme, 3) exploring the effects of polymorphisms on substrate specificity and stability, and 4) integrating these enzymatic properties into the Rosetta Enzyme Design method [10, 11]. The proposed research will therefore, not only focus on characterizing reaction mechanisms of PON1 at its active site, but also include dynamical information beyond this site, such that the redesigned enzyme will be more catalytic efficient and highly expressible. The resulting computational design will concurrently be tested and characterized in the wet-lab. The experimental biochemistry will be included as restraint information to optimize the designed cycle further. The research proposal is the interplay between theory, experiments, and computations which will facilitate a rapid progress for the proposed research. The candidate´s main career goals are to become a tenured, endowed professor at a Tier 1 research institution and to have a multidisciplinary research group that works on methodology developments and applications to environmental health sciences and biotechnology. She believe that in less than a decade, computational structural biology and cellular bioinformatics will have come together to advance research in protein engineering; at this point, in her research plans for the K01 fellowship, she aim to get the right breadth of expertise to be positioned precisely at that intersection. In this context, she is eager to take her computational expertise developed in the McCammon and Dobson laboratories and apply it to the enzyme design that Professor Baker, one of the world renowned expert in the field, is pursuing. The new Rosetta Enzyme Design is introduced and applied to re-engineer the human paraoxonase to be used as effective bioscavengers that sequester highly toxic organophosphate compounds commonly found in commercial products. This proposal thus has direct relevance impact in environmental protections and biotechnologies
Keywords: Active Sites; Agriculture; Algorithms; Amino Acids; aryldialkylphosphatase; Biochemistry; Bioinformatics; bioscavenger; Biotechnology; career; Catalysis; Cessation of life; Chemicals; Cholinesterase Inhibitors; Collaborations; conformer; design; Development; Ecosystem; Engineering; Ensure; Environmental Health; Environmental Protection; Enzymes; Equilibrium; esterase; Evolution; Exposure to; Fellowship; Flame Retardants; Gasoline; Generations; Genetic Polymorphism; Gluconolactonase; Goals; Health; Human; Human Engineering; Individual; Insecticides; Institution; Interdisciplinary Study; Laboratories; Letters; Link; Methodology; Methods; Mothers; Nature; novel strategies; Organophosphates; Performance; Pesticides; Phosphoric Triester Hydrolases; Physiological; Plastics; Population; Positioning Attribute; preference; Process; professor; Property; Protein Dynamics; Protein Engineering; Proteins; public health relevance; Reaction; Research; Research Project Grants; Research Proposals; research study; restraint; Role; Rubber; Serum; Site; Specificity; stem; structural biology; Substrate Specificity; Temperature; Testing; theories; Therapeutic; Toxic effect; Training; working group
Relevance: The new Rosetta Enzyme Design is introduced and applied to re-engineer the human paraoxonase to be used as effective bioscavengers that sequester highly toxic organophosphate compounds commonly found in commercial products. This proposal thus has direct relevance impact in environmental protections and biotechnologies
Project start date: 2010-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-09-040
5K01ES018854-02 (2011): $83580
CRCNS: INTEGRATIVE INFORMATION PROCESSING
M Jennifer, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01NS050942-07 from National Institute Of Neurological Disorders And Stroke
Abstract: Integrating sensory information from a variety of sources to produce motor commands is fundamental to human behavior. Impairments in multisensory and sensorimotor integration impact numerous aspects of human health, ranging from social interactions and communication to movements in a complicated environment. For example, directing gaze to the location of a sound is a complex information processing task requiring the conversion of auditory input signals into motor commands to move the eyes. This process is impaired in human neglect patients. Here, we propose a joint computational and experimental approach to illuminate this problem. Specifically, we will investigate how information about sound location is encoded in the spike trains of neurons in primate superior colliculus (SC), in comparison to structures that provide inputs to or receive an output from the SC, such as auditory cortex, intraparietal cortex, and the paramedian reticular formation. We will explore the reference frame (Aim 1) and coding format (Aim 2) of the representation of stimulus location. Of particular interest will be the relationship between visual and auditory representations we will evaluate quantitatively the similarity between these representations. In Aim 3, we will consider how these signals are "read out" into commands to move the eyes. This theoretical and experimental aim will test algorithms that could produce accurate motor commands to both visual and auditory targets despite differences in how these signals are encoded at earlier stages. These aims will enhance our understanding of neural processing from sensory input to motor output. The issues of multisensory and sensorimotor integration investigated here bear on a variety of neurological disorders such as those arising from stroke and other types of brain lesions. A better understanding of the transformation from sensory input to motor response will aid in identifying the pathophysiological substrates in neurological disorders with impaired sensorimotor integration. Problems involving multisensory and sensorimotor integration are implicated in a variety of neurological disorders including stroke, neglect, Parkinson´s disease, and autism. A better understanding of how sensory inputs of different modalities are transformed to produce motor commands will help us identify the pathophysiological substrates of these diseases. Ultimately, new therapies in which information from one sensory modality is used to compensate for deficiencies in another sensory modality may emerge from this research
Keywords: abducens nucleus; Address; Algorithms; Applications Grants; Auditory; Auditory area; auditory pathway; auditory stimulus; Autistic Disorder; awake; base; Behavior; Behavioral; Biological Models; Brain; Code; Complex; Computing Methodologies; Disease; Dyslexia; Ear structure; Environment; Equation; Eye; eye center; Eye Movements; Funding; gaze; Head; Health; Human; Impairment; Individual; information processing; interest; Joints; Knowledge; Lesion; Lighting; Location; Maps; Modality; Modeling; Monkeys; Motor; Motor output; Motor Pathways; Movement; multisensory; neglect; nervous system disorder; Neurons; nucleus reticularis; oculomotor; orbit muscle; Output; Parkinson Disease; Pathway interactions; Patients; Pattern; Pontine structure; Population; Primates; Process; Reading; receptive field; relating to nervous system; Relative (related person); Research; research study; response; Reticular Formation; Retina; Saccades; Schizophrenia; Sense Organs; Sensory; Sensory Process; Signal Transduction; simulation; Site; social communication; Social Interaction; sound; Source; Staging; Stimulus; stroke; Structure; superior colliculus Corpora quadrigemina; Techniques; Testing; Time; Training; Ursidae Family; Visual; visual stimulus; Work
Relevance: Problems involving multisensory and sensorimotor integration are implicated in a variety of neurological disorders including stroke, neglect, Parkinson´s disease, and autism. A better understanding of how sensory inputs of different modalities are transformed to produce motor commands will help us identify the pathophysiological substrates of these diseases. Ultimately, new therapies in which information from one sensory modality is used to compensate for deficiencies in another sensory modality may emerge from this research
Project start date: 2004-09-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01NS050942-07 (2011): $334425
OSPC MEDIATED EVASION OF THE INNATE IMMUNE RESPONSE BY BORRELIA BURGDORFERI
M Jennifer
University Of Missouri-columbiacity: Columbia country: United States (us)
Grant 5K08AI083744-03 from National Institute Of Allergy And Infectious Diseases
Abstract: Dr. Jennifer Hughes Hanks is a veterinary pathologist in the final stages of her residency training. She has a long-standing interest in the pathogenesis of infectious diseases, specifically emerging and foreign animal diseases. While Dr. Hughes Hanks has considerable training in the clinical diagnosis and behavior of a wide range of infectious diseases, her research training is limited. Her goal in the next four years is to develop the skills to become an independent researcher in the field of emerging infectious disease. This proposal describes a PhD training project which will take place in the Department of Pathobiology at the Univerisity of Missouri. The training will be supervised by Charles R. Brown, a well-established research scientist. The project will be focused on the pathogenesis of Borrelia burgdorferi, the causive agent of Lyme disease, in the mouse model. Since its discovery in the mid-1970s, Lyme disease has become the most common vector- borne infectious disease in the United States and is classified as an emerging infectious disease. While significant progress has been made in understanding the mechanisms of Lyme disease pathology, especially arthritis, little is known about the basic mechanisms of spirochete transmissibility and how it avoids immune clearance. Recent work in the mouse model has illustrated that surface lipoprotein antigens, specifically OspC, expressed by B. burgdorferi organisms are critical to the survival and dissemination of the spirochete in the mammalian host by evasion of the innate immune response. In this project, the cellular immune response will be quantified histologically during the early phase of in vivo infection by OspC-deficient spirochetes (Aim 1). The cytokine/chemokine alterations at the inoculation site of wild-type mice will be determined after challenge with OspC(-) B. burgdorferi mutants (Aim 2). Variations in survivability of OspC- deficient spirochetes will be examined in KC, CXCR2, MCP-1, and CCR2 cytokine knockout mice (Aim 3). At the completion of the project, Dr. Hughes will be better equipped to achieve her long-term career objective of aiding in national biosecurity efforts by helping to prevent the spread of emerging and foreign animal diseases
Keywords: Acute; Animal Diseases; Ankle; Antigens; Arthritis; Behavior; Biological Models; biosecurity; Bite; Black-legged Tick; Bladder; Blood; Borrelia burgdorferi; Cardiovascular system; career; Case Study; CCL2 gene; Cells; chemokine; chemokine receptor; Chronic; clinical Diagnosis; Communicable Diseases; Confocal Microscopy; cytokine; Development; Disease; Doctor of Philosophy; Dose; Ear structure; Emerging Communicable Diseases; Goals; Heart; Histologic; Hour; Human; IL8RB gene; Immune; immune clearance; Immune response; in vivo; Inbred C3H Mice; Inbred Strains Mice; Incidence; Infection; Infectious Diseases Research; Inflammatory; Inflammatory Response; interest; Investigation; Knockout Mice; Lipoproteins; Lyme Disease; Mediating; Membrane Proteins; Messenger RNA; Missouri; Morbidity - disease rate; mouse model; mutant; Neurologic; Order Spirochaetales; Organism; OspC protein; pathogen; Pathogenesis; Pathologist; Pathology; Phase; prevent; Principal Investigator; protein expression; Regulation; Research; Research Personnel; Research Training; Residencies; Resistance; response; Scientist; Site; skills; Skin; Source; Staging; Staining method; Stains; Structure; Surface; System; Tissues; Training; training project; United States; Variant; Vector-transmitted infectious disease; Wild Type Mouse; Work
Project start date: 2009-09-15
Project end date: 2013-09-29
Budget start date: 30-SEP-2011
Budget end date: 29-SEP-2012
PFA/PA: PA-06-512
5K08AI083744-03 (2011): $115840
PHYSICIAN RECOMMENDATION AND COLORECTAL CANCER SCREENING
M Jennifer, Professor
Henry Ford Health Systemcity: Detroit country: United States (us)
Grant 5R01CA112379-04 from National Cancer Institute
Abstract: Data from our own efforts and those of others indicate that different physicians discuss different things when recommending cancer screening. The U.S. Preventive Services Task Force (USPSTF) while not endorsing a specific style of physician-patient interaction, recently advocated for the use of shared decision-making when making preventive service recommendations to individual patients. We propose to use a mixed-method approach that includes both qualitative and quantitative data collection and analyses to understand the use and utility of different aspects of shared decision-making when physicians recommend CRC screening in primary care. First, we will use direct observation and audio-recording of routine health maintenance visits (n=900) to characterize the nature and content of CRC screening discussions in primary care (Aim 1). Results from these qualitative efforts will be used to derive quantitative measures characterizing physician-patient discussions of CRC screening in primary care. In the second stage, we will join these qualitatively derived measures characterizing physician-patient discussions of CRC screening with automated claims/laboratory data to determine their relationship to 12-month post-visit CRC screening use (Aim 2). A combined pre- and post-visit patient survey will allow us to assess the concordance of patient preferences for screening modality, information, and participation in decision-making with what occurs in the observed visit. We will then be able to evaluate the effect of these concordances on 12-month post-visit CRC screening use (Aim 3). We will use the Henry Ford Health System (HFHS), a large integrated delivery system serving Detroit and its surrounding suburbs, as the setting for these efforts. The diversity and size of the HFHS primary care physician and patient populations combined with the comprehensive, existing automated data systems makes this an ideal environment in which to conduct the proposed work. By joining detailed accounts of the contribution of both physicians and patients to CRC screening discussions in the real world of primary care with subsequent CRC screening use and patient reported preferences, results from the proposed project will inform a new generation of interventions aimed at improving CRC screening participation. They will provide valuable information for training both physicians and patients how to effectively discuss CRC screening as well as facilitate the development of decision aides and policies for diverse populations
Keywords: Accounting; Active Follow-up; Address; Adherence; Adherence (attribute); Advisory Committees; Advocate; Affect; base; Benefits and Risks; Cancer Screening for Patients; Caring; Characteristics; colorectal cancer screening; Communication; Data; Data Collection; Decision Making; Development; diverse populations; early cancer detection; early detection of colorectal cancer; Elements; Environment; Ethics; follow-up; Frequencies (time pattern); Frequency; Future; Gender; Generations; Health; Health system; Heterogeneity, Population; heterogeneous population; improved; In element; Indium; Individual; Information Systems; Information Technology Systems; Integrated Delivery Systems; interest; Intervention; Intervention Strategies; interventional strategy; Investigators; IT Systems; Laboratories; Link; Maintenance; Maintenances; Measures; Methods; Modality; Nature; novel; patient population; Patient Preferences; Patients; Physicians; Policies; Population; Population Heterogeneity; Position; Positioning Attribute; preference; Preventive; Primary Care; Primary Care Physician; Primary Health Care; Primary Healthcare; Process; programs; Programs (PT); Programs [Publication Type]; PROV; Provider; Race; Racial Group; Recommendation; Reporting; Research Personnel; Researchers; Role; screening; Screening for cancer; Screening for Colorectal Cancer; Screening procedure; screenings; Services; shared decision making; social role; Staging; Stocks, Racial; suburb; Survey Instrument; Surveys; Systems, Data; Task Forces; Testing; Training; Translations; Visit; Work
Project start date: 2006-07-05
Project end date: 2011-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2011
PFA/PA: PAR-04-036
5R01CA112379-04 (2009): $292821