TRAINING IN NEUROINFLAMMATION AND GLIAL CELL BIOLOGY
Michael Kerry O´banion, Associate Professor
University Of Rochester, 518 Hylan Bldg., Box 270140, Rochester, Ny 14627
Grant 5T32NS051152-05 from National Institute Of Neurological Disorders And Stroke
Abstract: There is increasing recognition that inflammatory processes underlie many acute and chronic diseases, including those of the central nervous system. In particular, the glial and vascular components of the brain play significant and unique roles in inflammatory processes, both as sources of inflammatory mediators and as targets for local innate and acquired immune responses. Moreover, there is increasing recognition of the importance for glia in all aspects of brain function, ranging from normal homeostasis to repair and repopulation following injury. Understanding these processes and their implications for diseases requires interactions that cross the classic disciplines of Neuroscience, Immunology, and Developmental Cell Biology, with focused training in molecular/immunological signaling and glial cell biology. Building on strengths of an outstanding group of faculty at the University of Rochester Medical Center, this grant application outlines a proposed program for pre and postdoctoral students that provides the cross-disciplinary exposure and highly interactive research environments required for scientists to access the fields of Neuroinflammation and Glial Cell Biology
Keywords: Cellular biology; Glia; Glial Cells; Kolliker`s reticulum; Neuroglia; Neuroglial Cells; Non-neuronal cell; Training; cell biology; nerve cement; neuroinflammation
Project start date: 2005-07-01
Project end date: 2010-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-02-109
5T32NS051152-05 (2009): $116208
Sponsored Links Excellgen http://Excellgen.com
Training In Neuroinflammation And Glial Cell Biology
Michael Kerry O´banion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
517 Hylan Bldg., Box 270140
rochester, Ny 14627
Grant 5T32NS051152-04 from National Institute Of Neurological Disorders And Stroke IRG: NST
Abstract: There is increasing recognition that inflammatory processes underlie many acute and chronic diseases, including those of the central nervous system. In particular, the glial and vascular components of the brain play significant and unique roles in inflammatory processes, both as sources of inflammatory mediators and as targets for local innate and acquired immune responses. Moreover, there is increasing recognition of the importance for glia in all aspects of brain function, ranging from normal homeostasis to repair and repopulation following injury. Understanding these processes and their implications for diseases requires interactions that cross the classic disciplines of Neuroscience, Immunology, and Developmental Cell Biology, with focused training in molecular/immunological signaling and glial cell biology. Building on strengths of an outstanding group of faculty at the University of Rochester Medical Center, this grant application outlines a proposed program for pre and postdoctoral students that provides the cross-disciplinary exposure and highly interactive research environments required for scientists to access the fields of Neuroinflammation and Glial Cell Biology
Project start date: 2005-07-01
Project end date: 2010-06-30
5T32NS051152-04 (2008): $193914
Grants awarded to Michael Kerry O´banion
Medical Scientist Training Program Grant
Michael Kerry O´banion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
517 Hylan Bldg., Box 270140
rochester, Ny 14627
Grant 5T32GM007356-33 from National Institute Of General Medical Sciences IRG: BRT
Abstract: The University of Rochester has a long history of training physician-scientists, with numerous alumni in leadership positions at academic medical centers. Fueled by a ten-year $550 million strategic plan initiated in 1997, the Medical Center is enjoying unprecedented growth with new space for 80 research-intensive faculty organized into highly interactive groups. The combination of a rigorous and innovative educational curriculum with a rich research environment staffed by superlative faculty provides outstanding opportunities for the training of physician-scientists in biomedical sciences and for its meaningful translation to patient care. To capitalize on these opportunities, the University has committed its MD/PhD program to an expansion, which began two years ago with the matriculation of three additional highly qualified students. As evidence of our continuous effort to create the optimal training experience, we have instituted a new administrative structure that provides greater oversight of the program and an advisory system that pairs students with career physician-scientists for their entire tenure in the program. Improved integration of medical and graduate curricula has been achieved by increasing the time available for graduate work in all phases of training, creating MSTP specific problem-based learning groups, and introducing Scientific Reasoning in Medicine, a class for students in the first two program years. Moreover, rigorous MD/PhD specific curricula have been instituted for all PhD programs, including new programs in Biomedical Engineering, Epidemiology, Health Services Research, and Biostatistics and Computational Biology. Coupled with the University of Rochester´s commitment, funds from this renewal will ensure that our most qualified participants will develop the skills and insights to initiate and lead the translation from laboratory bench or specialized analyses to patient care during this dynamic era of biomedical research
Project start date: 1976-11-01
Project end date: 2009-06-30
5T32GM007356-33 (2008): $512282
5T32GM007356-35 (2010): $584813
2T32GM007356-34 (2009): $533655
3T32GM007356-34S1 (2009): $48514
NEUROINFLAMMATION IN CNS RADIATION INJURY: IL-1 & COX-2
Michael Kerry O´banion, Associate Professor
University Of Rochester, 518 Hylan Bldg., Box 270140, Rochester, Ny 14627
Grant 5R01CA114587-05 from National Cancer Institute
Abstract: Successful management of tumors in the brain, head and neck is limited by potential damage to normal brain tissue caused by ionizing radiation. Although early symptoms are treatable, the delayed onset of cognitive and motor dysfunction s irreversible and contributes to morbidity and mortality. Neuroinflammatory changes, including activation of glial cells and expression of cytokines and other proinflammatory mediators, are a consistent feature of brain irradiation injury. Moreover, successful administration of corticosteroids for treatment of acute and chronic symptoms implicates the importance of inflammation-related events in radiation-induced injury and/or vulnerability. Based on their key roles in neuroinflammation and brain injury, and preliminary studies detailed in this proposal, we hypothesize that IL-1b and COX-2 are critical mediators of brain inflammation following radiation exposure. Studies in numerous systems, including our own investigations in whole brain, place COX-2, working through production of PGE2, as a downstream mediator of IL-1b action. Together, these findings suggest the hypothesis that neuroinflammation following radiation injury is dependent on an IL-1b/COX-2 pathway. Moreover, interference with this path may confer protection to normal tissue radiation injury. Three specific aims are proposed to establish the roles of IL-1 and COX in early and late brain tissue reaction following radiation exposure. Aim 1 utilizes 3 lines of knockout mice with defective IL-1 signaling pathways (null for IL-1R1, IL-1a, and IL-1b). Aim 2 will confirm the role of IL-1 by investigating brain irradiation responses in somatic mosaic mice engineered to regionally overexpress IL-1b or IL-1Ra. The final aim utilizes pharmacological and gene deletion approaches to investigate the specific role of COX-2 in CNS radiation responses. This work will provide a better understanding of the molecular and cellular mechanisms contributing to early and delayed effects, and may directly implicate specific targets for prevention and treatment of brain radiation injury
Keywords: (5Z, 8Z, 11Z, 14Z)-Icosa-5, 8, 11, 14-tetraenoate, hydrogen-donor[{..}]oxygen oxidoreductase; Acquired brain injury; Active Follow-up; Acute; Adipogenesis Inhibitory Factor; Adrenal Cortex Hormones; Arachidonic Acid Cyclooxygenase; Astrocytes; Astrocytus; Astroglia; Attention; Blood Vessels; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; Brain; Brain Injuries; Brain Neoplasia; Brain Neoplasms; Brain Tumors; COX; COX-1; COX-1 protein; COX-2 protein; COX1; COX2; COX2 enzyme; COX2 inhibitor; COX3; Cells; Chronic; Cognitive; Corticoids; Corticosteroids; Coxibs; Cranial Irradiation; Cyclo-Oxygenase; Cyclo-Oxygenase-1; Cyclo-Oxygenase-2; Cyclooxygenase; Cyclooxygenase 2 Inhibitors; Cyclooxygenase 3; Cytokines, Chemotactic; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Demyelinations; Dinoprostone; Dose; Dropsy; Dysfunction; ELISA; Edema; Electromagnetic Radiation, Ionizing; Encephalitis; Encephalon; Encephalons; Engineering; Engineerings; Enzyme-Linked Immunosorbent Assay; Event; Family member; Fatty Acid Cyclo-Oxygenase; Fatty Acid Cyclooxygenase; Functional disorder; GFP; Gene Deletion; Generations; Genetic; Genetics, in situ Hybridization; Glia; Glial Cells; Green Fluorescent Proteins; Head and Neck; Head and neck structure; Homologous Chemotactic Cytokines; Hortega cell; Hydroperoxide Cyclase; Hydrops; IL-1; IL-11; IL1; IL1 Receptors; IL11; INFLM; Image Analyses; Image Analysis; Immune; In Situ Hybridization; Inflammation; Inflammation, Brain; Inflammatory Response; Injury; Intercrines; Interleukin I; Interleukin-1; Interleukin-1 Receptors; Interleukin-11; Interleukins; Investigation; Ionizing radiation; Isoforms; Knockout Mice; Kolliker`s reticulum; Link; Lipids; Lymphocyte-Stimulating Hormone; Macrophage Cell Factor; Mammals, Mice; Measurement; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Messenger RNA; Mice; Mice, Knock-out; Mice, Knockout; Microglia; Molecular; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Motor; Murine; Mus; Myelin Basic Proteins; NS-398; Necrosis; Necrotic; Nervous System, Brain; Neural Growth; Neurodegenerative Diseases; Neurodegenerative Disorders; Neuroglia; Neuroglial Cells; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neuronal Growth; Non-neuronal cell; Normal Tissue; Normal tissue morphology; Null Mouse; PGE2; PGE2 alpha; PGE2alpha; PGH Synthase; PGH Synthase 1; PGH Synthase 2; PGH2 Synthetase; PGHS-1; PGHS-2; PGHS2; PHS II; PHS1; PTGS1; PTGS2; Pathogenesis; Pathway interactions; Peripheral; Physiopathology; Prevention; Process; Production; Prosta-5, 13-dien-1-oic acid, 11, 15-dihydroxy-9-oxo-, (5Z, 11alpha, 13E, 15S)-; Prostaglandin Cyclo-Oxygenase; Prostaglandin Cyclooxygenase; Prostaglandin E2; Prostaglandin E2 alpha; Prostaglandin E2alpha; Prostaglandin Endoperoxide Synthetase; Prostaglandin G-H Synthase; Prostaglandin G/H Synthase 1; Prostaglandin G/H Synthase 2; Prostaglandin G/H Synthase and Cyclooxygenase; Prostaglandin H Synthase; Prostaglandin H2 Synthase; Prostaglandin H2 Synthase 1; Prostaglandin H2 Synthase 2; Prostaglandin H2 Synthetase; Prostaglandin Production; Prostaglandin Synthase; Prostaglandin Synthetase; Prostaglandin-Endoperoxide Synthase; Prostaglandin-Endoperoxide Synthase 1; Prostaglandin-Endoperoxide Synthase 2; Prostaglandins; Prostanoids; Protein Isoforms; RNA, Messenger; ROC Analysis; Radiation; Radiation Injuries; Radiation Toxicity; Radiation-Induced Change; Radiation-Ionizing Total; Reaction; Receptors, IL-1; Receptors, Interleukin-1; Relative; Relative (related person); Role; SIS cytokines; Signal Pathway; Staging; Symptoms; System; System, LOINC Axis 4; T Helper Factor; Testing; Therapeutic Corticosteroid; Time; Transplantation; Trauma; Up-Regulation; Up-Regulation (Physiology); Upregulation; Work; base; brain damage; brain irradiation; brain irradiation injury; brain lesion (from injury); brain radiation; brain radiation injury; brain tissue; cell type; cerebrovascular; chemoattractant cytokine; chemokine; cranial radiation; cyclo-oxygenase I; cyclo-oxygenase II; cyclooxygenase 1; cyclooxygenase 2; cytokine; experiment; experimental research; experimental study; follow-up; gene deletion mutation; gitter cell; image evaluation; in situ Hybridization Staining Method; indexing; inhibitor; inhibitor/antagonist; irradiation; lymphocyte activating factor; mRNA; mesoglia; microglial cell; microgliocyte; nerve cement; neurodegenerative illness; neurogenesis; neuroinflammation; neutralizing antibody; overexpression; pathophysiology; pathway; perivascular glial cell; prostaglandin H synthase-1; prostaglandin H synthase-2; ray (radiation); research study; response; social role; substantia alba; transplant; tumors in the brain; unspecified interleukin; vascular; white matter
Project start date: 2005-02-01
Project end date: 2010-06-30
Budget start date: 1-JAN-2009
Budget end date: 30-JUN-2010
5R01CA114587-05 (2009): $292135
AMERICAN PHYSICIAN SCIENTISTS ASSOCIATION ANNUAL MEETING
Michael Kerry O´banion, Associate Professor
American Physicians Scientists Assn, 211 W Green St, #4, Urbana, Il 61801-3277
Grant 5R13CA136301-02 from National Cancer Institute
Abstract: Physician-scientists are uniquely positioned to conduct innovative medical research along the entire continuum of basic, clinical, patient-oriented, and population-based sciences. Although currently preserved from extinction, the physician-scientist remains threatened today, in part, due to obstacles that exist along the physician-scientist career pathway. Among these obstacles are the long training period, personal debt, limited research funding, lack of mentoring, and the uncertainty of a successful career. With such a broad scope of potential career tracks available, it is crucial to have career development opportunities targeted specifically to this important cadre of future scientists. Prior to the Inaugural APSA Annual Meeting in April, 2005, there was no authoritative avenue for American physician-scientists in training to obtain deep insight into the career paths that are available to them in all career sectors (NIH, industry, and academia) and in broad medical disciplines. The APSA Annual Meeting serves as an excellent opportunity for current and prospective physician-scientists in training to learn about the diverse career options available to them. This meeting is held concurrently with the Joint Meeting of the American Society for Clinical Investigation (ASCI) and the Association of American Physicians (AAP) (two of the premier organizations dedicated to the physician-scientist). Through this close collaboration, APSA members are able to interact directly with well established physician-scientists from all areas of medicine and science. This application seeks funds to provide continuity of support for the 3-day National APSA Annual Conference that brings together over 200 trainees interested in careers combining science and medicine, at the following stages of training MD, DO, PhD, Residents / Fellows and undergraduates. The conference provides a structured environment to disseminate career advice from established physician-scientists in all career sectors, to promote the development of mentoring relationships, and to foster community building amongst physician-scientist trainees. Objectives 1) To address career development issues for physician-scientist trainees; 2) To provide mentoring and networking opportunities for future physician-scientists, and; 3) To provide additional support for women, under-represented minorities, and non-PhD trainees who are currently in the physician-scientist career track. APSA Annual Meeting Physician-scientists are a critical component of the medical research enterprise and their training provides them with the unique ability to apply clinical knowledge to their research efforts to improve the treatment of human disease 1-5. The decline of physician-scientists in the United States is well documented and numerous NIH initiatives have been put in place to preserve this rarified group 6-8. The APSA Annual Meeting will directly support the future of physician scientists in the United States by providing current trainees with an unparalleled perspective on the career opportunities available to them and by providing numerous opportunities for vertical and horizontal mentorship
Keywords: Academia; Address; American; Area; Articulation; Clinical; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Communities; Development; Discipline; Doctor of Philosophy; Environment; Extinction; Extinction (Psychology); Fostering; Funding; Future; Industry; Joints; Knowledge; Learning; Medical; Medical Research; Medicine; Mentors; Mentorship; NIH; National Institutes of Health; National Institutes of Health (U.S.); Pathway interactions; Ph.D.; PhD; Physicians; Position; Positioning Attribute; Research; Research, Medical; Science; Science of Medicine; Scientist; Societies; Staging; Structure; Training; Uncertainty; Underrepresented Minority; United States; United States National Institutes of Health; Woman; behavioral extinction; career; career development; clinical investigation; conference; doubt; human disease; improved; innovate; innovation; innovative; insight; interest; meetings; member; pathway; patient centered; patient oriented; population based; prospective; public health relevance; symposium; under-represented minority; underserved minority
Relevance: APSA Annual Meeting Physician-scientists are a critical component of the medical research enterprise and their training provides them with the unique ability to apply clinical knowledge to their research efforts to improve the treatment of human disease 1-5. The decline of physician-scientists in the United States is well documented and numerous NIH initiatives have been put in place to preserve this rarified group 6-8. The APSA Annual Meeting will directly support the future of physician scientists in the United States by providing current trainees with an unparalleled perspective on the career opportunities available to them and by providing numerous opportunities for vertical and horizontal mentorship
Project start date: 2009-04-22
Project end date: 2014-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-08-149
5R13CA136301-02 (2010): $56949
NEUROINFLAMMATION AND GLIAL ROS IN METHAMPHETAMINE NEUROTOXICITY
Michael Kerry O´banion, Associate Professor
University Of Rochester, 518 Hylan Bldg., Box 270140, Rochester, Ny 14627
Grant 5R01DA026009-02 from National Institute On Drug Abuse
Abstract: Neurological symptoms with methamphetamine (METH) toxicity of the nigrostriatal system, both in rodent models and in drug abusers, are associated with neuroinflammation, a fundamental reaction to brain injury characterized by activated microglia and astrocytes, local expression of inflammatory mediators, and possible infiltration of peripheral cells such as monocytes. This prominent and local tissue response most likely represents an adaptive and restorative repair process. Yet reminiscent of many inflammatory conditions in peripheral diseases, neuroinflammation can also contribute to the pathophysiology of CNS disorders. Thus observations of neuroinflammation in the setting of METH neurotoxicity raise questions about the contribution of glial directed inflammation to neuronal damage as well as the possible mechanisms underlying this association. One such mechanism is oxidative stress, which is known to occur in both METH toxicity and neuroinflammation. Among HIV infected individuals, METH abuse is associated with significant enhancement of HIV encephalitis, greater neuropathology, and increased expression of inflammation-associated genes. Thus neuroinflammation represents a factor common to both METH exposure and CNS HIV infection that may underlie the enhanced disease and neuropathology seen when these two risk factors coexist. One of the major driving forces in CNS inflammation is the proinflammatory cytokine interleukin (IL)-1¿, which is produced by activated microglia. Among its many actions, IL-1¿ promotes phenotypic activation of astrocytes leading to expression of other inflammatory mediators including chemokines, which facilitate CNS infiltration by monocytes and other blood-borne cells. Moreover, there is clear evidence that IL-1 is an important contributor to neuronal damage in several CNS injury and disease models. We have recently developed a transgenic mouse model that provides temporal and spatial control of sustained IL-1¿ expression. We propose using this mouse to test the hypothesis that coexistent neuroinflammation enhances METH-induced damage in the ventral midbrain dopaminergic system. A corollary hypothesis is that attenuation of neuroinflammation will protect against METH neurotoxicity. Finally, we hypothesize that one mechanism underlying the association between neuroinflammation and METH toxicity is production of microglial/ macrophage derived reactive oxygen species (ROS). To explore these hypotheses, we will 1) quantify striatal dopaminergic nerve terminal toxicity elicited by METH exposure in the presence of sustained neuroinflammation; 2) determine whether abrogation of IL-1 signaling reduces neurotoxicity following METH exposure, and 3) characterize oxidant injury in METH and METH + neuroinflammation elicited neurotoxicity. By better understanding the role of neuroinflammation in METH-associated neurotoxicity, we may be able to develop strategies to curb the neurological side effects of METH abuse, particularly when associated with conditions like HIV where neuroinflammation is prominent
Keywords: 3, 4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1, 2-benzenediol; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Acquired brain injury; Active Oxygen; Adverse effects; Animals; Antioxidants; Applications Grants; Astrocytes; Astrocytus; Astroglia; Attenuated; Behavioral; Benzeneethanamine, N, alpha-dimethyl-, (S)-; Biochemical; Blood; Blood monocyte; Body Tissues; Bone Marrow; Brain Injuries; C57BL/6 Mouse; CNS Diseases; CNS Injury; CNS disorder; Cell Body; Cell Communication and Signaling; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cells; Central Nervous System Diseases; Central Nervous System Disorders; Central Nervous System Injury; Corpus Striatum; Corpus striatum structure; Correlative Study; Crystal Meth; Cytokines, Chemotactic; DA Neuron; Deoxyephedrine; Desoxyephedrine; Disease; Disease model; Disorder; Dopamine; Dopamine neuron; Dose; Drug abuser; Drug usage; Drugs, Illicit; Dysfunction; Encephalitis; Enzymes; Evaluation; Free Radicals; Functional disorder; Genes; Grant Proposals; Grants, Applications; HIV; HIV Infections; HIV encephalitis; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Health; Histologic; Histologically; Homologous Chemotactic Cytokines; Hortega cell; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Hydroxytyramine; IHC; IL-1; IL-1 inhibitor, urine; IL-1ra; IL1; IL1 febrile inhibitor; IL1RN; INFLM; Illicit Drugs; Immunohistochemistry; Immunohistochemistry Staining Method; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammation, Brain; Inflammatory; Injury; Injury of central nervous system; Intercrines; Interleukin I; Interleukin-1; Interleukin-1 Receptor Antagonist; Interleukins; Intracellular Communication and Signaling; LAV-HTLV-III; Laboratories; Lentiviral Vector; Lentivirus Vector; Locomotor Activity; Lymphadenopathy-Associated Virus; Lymphocyte-Stimulating Hormone; Macrophage Cell Factor; Mammals, Mice; Marrow monocyte; Measures; Memory; Mesencephalon; Messenger RNA; Methamphetamine; Methylamphetamine; Mice; Microglia; Mid-brain; Midbrain; Midbrain structure; Misuses drugs; Motor Activity; Murine; Mus; N-Methylamphetamine; NADPH Oxidase; Nerve; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurocyte; Neurologic; Neurological; Neuronal Injury; Neurons; Outcome; Oxidants; Oxidative Stress; Oxidizing Agents; Oxygen Radicals; Peripheral; Physiopathology; Pro-Oxidants; Problem drug user; Process; Production; Proteins; Protocol; Protocols documentation; RNA, Messenger; RT-PCR; RTPCR; Reaction; Reactive Oxygen Species; Receptor Protein; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Rodent Model; Role; SIS cytokines; Series; Signal Transduction; Signal Transduction Systems; Signaling; Striate Body; Striatum; Substantia Nigra; Substantia nigra structure; Symptoms; System; System, LOINC Axis 4; T Helper Factor; T-Lymphotropic Virus Type III Infections, Human; Testing; Time; Tissues; Toxic effect; Toxicities; Transgenic Mice; Treatment Side Effects; Virus-HIV; anakinra; anti-oxidant; attenuation; biological signal transduction; brain damage; brain lesion (from injury); cell body (neuron); central nervous system injury; chemoattractant cytokine; chemokine; cytokine; disease/disorder; disorder model; dopaminergic neuron; driving force; drug use; electron acceptor; experiment; experimental research; experimental study; gene product; gitter cell; indexing; interleukin 1 inhibitor, urine; interleukin 1 receptor antagonist protein; lymphocyte activating factor; mRNA; macrophage; mesoglia; meth exposure; methamphetamine abuse; methamphetamine exposure; microglial cell; microgliocyte; monocyte; mouse model; neural cell body; neuroinflammation; neuron injury; neuron toxicity; neuronal; neuronal cell body; neuronal toxicity; neuropathology; neurotoxicity; nigrostriatal system; object recognition; oxidative damage; pathophysiology; perivascular glial cell; primary outcome; receptor; repair; repaired; research study; response; reverse transcriptase PCR; side effect; social role; soma; striatal; therapy adverse effect; treatment adverse effect; unspecified interleukin; urine-derived IL1 inhibitor
Relevance: The use of methamphetamine is a major health issue that leads to serious and long-lasting brain injury. This grant application explores the role of brain inflammation, a feature evoked by methamphetamine drug use, in promoting damage. By better understanding the role of inflammation in this process, we may be able to develop strategies for curbing brain damage. These efforts may be particularly important in HIV-infected individuals who also use illicit drugs, since HIV alone evokes neuroinflammation
Project start date: 2009-08-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: RFA-DA-08-014
5R01DA026009-02 (2010): $330365
INTERLEUKIN-1: A MEDIATOR OF NEUROINFLAMMATION AND ALZHEIMER´S NEUROPATHOGENESIS
Michael Kerry O´banion, Associate Professor
University Of Rochester, 518 Hylan Bldg., Box 270140, Rochester, Ny 14627
Grant 5R01AG030149-04 from National Institute On Aging
Abstract: Neuroinflammation, characterized by activated microglia and astrocytes and local expression of a wide range of inflammatory mediators, is a fundamental reaction to brain injury, whether by trauma, stroke, infection, or neurodegeneration. This local tissue response is surely part of a repair and restorative process. Yet, like many inflammatory conditions in peripheral diseases, neuroinflammation can contribute to the pathophysiology of CNS disorders. For example, in Alzheimer´s disease (AD), glial-driven inflammatory responses to A¿ deposition are traditionally thought to promote neurodegeneration. However, more recent data suggests a more complex picture for the role of neuroinflammation in this disease. One of the key players in CNS inflammation is the proinflammatory cytokine interleukin (1L)-1¿, which is produced by activated microglia and is found elevated in AD. The overriding hypothesis for this proposal is that IL-1 plays a driving force in neuroinflammation and as such, has significant impact in Alzheimer´s disease where IL-1 levels are chronically elevated. In order to test this hypothesis, we have developed several new transgenic mouse lines designed to provide sustained and localized expression of IL-1¿ or IL-1ra, at an age of our choosing, and without developmental compensation that is often seen in standard transgenic models. As described in preliminary data, induction of IL-1 production leads to a profound and sustained neuroinflammatory response. Combined with other genetic, cellular, and pharmacological approaches the studies proposed with these mice should provide new insight into the role of IL-1 in chronic neuroinflammatory disorders, particularly Alzheimer´s disease. Our three aims are first, to further characterize the neuroinflammatory changes associated with sustained IL-1¿ expression; second, to explore the effects of IL-1¿ on neuropathological hallmarks present in Alzheimer´s disease (both plaques and tangles) using two AD mouse models; and third, to complement these later studies of AD neuropathogenesis by counteracting IL-1´s actions in these models. Together these three aims will provide a better understanding of IL-1´s role in AD and neuroinflammation in an in vivo setting. Such information speaks directly to the development and implementation of immunomodulatory therapies for the treatment and prevention of Alzheimer´s disease, a major public health challenge for our aging society
Project start date: 2007-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
5R01AG030149-04 (2010): $306292
5R01AG030149-03 (2009): $309386
1R01AG030149-01 (2007): $298536
Sponsored Links Excellgen http://Excellgen.com
IL-1 INDUCED MEDIATORS OF CNS INFLAMMATION AND AD-- COX-
Michael Kerry O´banion, Associate Professor
Neurologyuniversity Of Rochester
517 Hylan Bldg., Box 270140
rochester, Ny 14627
Grant 5R01NS033553-07 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: adapted from applicant´s ) Inflammation-related changes are a prominent part of the CNS response to acute injury, infection, and chronic neurodegenerative disease. Numerous studies indicate that attenuation of CNS inflammation may be beneficial in treating CNS disorders, including Alzheimer´s disease (AD). Microglia and astrocytes play a significant role in the initiation and maintenance of CNS inflammation by producing a wide-range of inflammation-related gene products. Elaboration of inflammatory responses elicited by both acute and chronic stimuli depends on key molecular players that drive interactions among cells. One of these players is IL-1 beta proinflammatory cytokine strongly implicated in acute CNS inflammation as well as AD. Based on studies of peripheral inflammation, another key player is likely to be prostaglandin E2 (PGE2) produced by the inflammation-responsive protein, cyclooxygenase-2 (COX-2), one of two isoforms of the obligate enzyme for prostaglandin biosynthesis. COX-2 is made in brain and can be induced by IL-1 beta and other proinflammatory cytokines in astrocytes and microglia. Moreover, preliminary studies indicate that selective inhibition of COX-2 attenuates the expression of inflammation-related genes following acute CNS injury. Based on these findings and epidemiological evidence that inhibitors of cyclooxygenase may be beneficial in AD, this competitive renewal focuses on the role of COX-2 in CNS inflammation. The hypothesis that COX-2 derived prostaglandins are required for elaboration of acute as well as chronic local inflammatory responses in the central nervous system will be tested in three different model systems. The first specific aim will characterize direct influences of COX-2 and PGE2 on expression of IL-1 beta responsive genes in primary cultures of human and murine astrocytes. In the second specific aim, the contributions of COX-2 and PGE2 to an acute inflammatory cascade elicited by cortical injection of IL-1 beta will be established. In the third and fmal specific aim, COX-2 specific inhibitors will be employed in double transgenic PS-1/APP mice to ascertain the role of COX-2 in chronic CNS inflammation secondary to Abeta deposition. Together, these studies examine the role of COX-2 and increased prostaglandin production in CNS inflammation and a model of Alzheimer´s disease. This work will provide a clearer understanding of the mechanisms by which anti-inflammatory drugs influence AD and may reveal new avenues for therapeutic intervention. Moreover, these studies have relevance to pathological processes occurring in head trauma, stroke, and other neurodegenerative diseases where gliosis and inflammation-related changes take place
Keywords: enzyme activity, gliosis, inflammation, interleukin 1, prostaglandin E, prostaglandin endoperoxide synthase Alzheimer`s disease, amyloid protein, astrocyte, brain injury, cell death, cytotoxicity, disease /disorder model, enzyme inhibitor, fatty acid biosynthesis, gene expression, messenger RNA, monoclonal antibody, neural degeneration, neutralizing antibody human tissue, laboratory mouse, polymerase chain reaction, tissue /cell culture, transgenic animal
Project start date: 2000-04-28
Project end date: 2003-03-31
5R01NS033553-07 (2001): $358875
MEDICAL SCIENTIST TRAINING GRANT
Michael Kerry O´banion, Associate Professor
Dentistryuniversity Of Rochester
517 Hylan Bldg., Box 270140
rochester, Ny 14627
Grant 5T32GM007356-25 from National Institute Of General Medical Sciences IRG: CMBD
Project start date: 1976-11-01
Project end date: 2001-07-31
5T32GM007356-25 (2000): $420748