Training In Neuroinflammation And Glial Cell Biology
Michael Kerry Obanion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
Grant 5T32NS051152-05 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
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Grants awarded to Michael Kerry Obanion
Medical Scientist Training Program Grant
Michael Kerry Obanion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
Grant 2T32GM007356-34 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 contributing to biomedical research and assuming leadership positions at academic medical centers. There is a continued and growing need for physician-scientists, who serve a unique role in translating research discoveries to the clinic and bringing clinical experiences to the laboratory bench. The main objective of the University of Rochester MSTP is to provide a unique and integrated environment for the rigorous and efficient training of future physician-scientists. This is accomplished by immersion in basic science and clinical exposure through all program years combined with a period of focused research leading to the PhD. Degrees are offered in a wide range of areas that take advantage of the University´s highly collaborative and interdisciplinary environment, including basic biomedical sciences with emphasis on specific organ systems, Biomedical Engineering, population based degrees in Biostatistics, Epidemiology and Health Services Research, and College-based programs such as Biology and Chemistry. As described in this application, our institutional environment continues to be invigorated by growth in outstanding faculty, resources and infrastructure, resulting in significant expansion of training opportunities. Most recently, this includes development of a Clinical Translational Science Institute (CTSI), supported in part by a CTSA granted in 2006. The CTSI provides myriad opportunities that enhance the MSTP, including funded slots for the PhD years of MD-PhD training and a new PhD program in Translational Biomedical Science. The medical school continues its commitment to the MSTP, increasing the number of incoming slots from 2-3 to 8 each year and supporting new initiatives to enhance training and recruitment activities. We have been successful in filling these slots with highly motivated students who are passionate about biomedical research; the net effect is a doubling of our program size since 2001. Coupled with the University of Rochester´s commitment, funds from this renewal will ensure that these individuals develop the skills and insights to initiate and lead the translation from science to human health during this dynamic era of biomedical research. RELEVANCE There is a great societal need for physician-scientists who work at the interface of clinical patient care and scientific investigation. The MSTP at the University of Rochester equips future physician-scientists with an in depth understanding of medicine and a rigorous research experience, allowing them to pursue careers that fill important positions in academic medicine and translate research discoveries to health improvement
Project start date: 1976-11-01
Project end date: 2014-06-30
Neuroinflammation In CNS Radiation Injury: IL-1 &; COX-2
Michael Kerry Obanion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
Grant 5R01CA114587-05 from National Cancer Institute IRG: ZRG1
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: central nervous system neoplasm, inflammation, interleukin 1, neoplasm /cancer radiation therapy, prostaglandin endoperoxide synthase, radiobiology, therapy adverse effect cyclooxygenase inhibitor, cytokine receptor, ionizing radiation, isozyme, myelin basic protein, myelinopathy, neurogenesis, prostaglandin E, radiation dosage, radiopharmacology, radioprotective agent enzyme linked immunosorbent assay, genetically modified animal, green fluorescent protein, in situ hybridization, laboratory mouse
Project start date: 2005-02-01
Project end date: 2009-12-31
American Physician Scientists Association Annual Meeting
Michael Kerry Obanion, Associate Professor
American Physicians Scientists Assn
Grant 1R13CA136301-01A1 from National Cancer Institute IRG: ZCA1
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 Project Narrative 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
Neuroinflammation And Glial ROS In Methamphetamine Neurotoxicity
Michael Kerry Obanion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
Grant 1R01DA026009-01 from National Institute On Drug Abuse IRG: ZDA1
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)-12, which is produced by activated microglia. Among its many actions, IL-12 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-12 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 and establish the contribution of microglial vs. infiltrating macrophages to this process. 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. 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
Interleukin-1: A Mediator Of Neuroinflammation And Alzheimer´s Neuropathogenesis
Michael Kerry Obanion, Associate Professor
Anatomy And Neurobiologyuniversity Of Rochester
Grant 5R01AG030149-03 from National Institute On Aging IRG: CNBT
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 Aa 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)-1a, 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-1a 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-1a expression; second, to explore the effects of IL-1a 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
Keywords: Alzheimer`s disease, interleukin 1, model, role aging, apoptosis, astrocyte, birth, bone marrow, brain, brain injury, cell, central nervous system disorder, chronic disease /disorder, complement, conditioning, cytokine, disease /disorder model, disease /disorder proneness /risk, family, gene, genetically modified animal, genetics, hippocampus, indexing, infection, inflammation, injury, insight, laboratory mouse, lead, ligand, microglia, motivation, neural degeneration, neuron, pathology, play, prevention, public health, receptor, recombinase, reduction, stroke, success, therapy, thinking, tissue, transfection, trauma
Project start date: 2007-04-01
Project end date: 2012-03-31