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
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Michael Kerry Obanion
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