Role of PGE2 receptors in the aging brain after intracerebral hemorrhage

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DESCRIPTION (provided by applicant): The long-term goal of this K01 award is to prepare the applicant for a career as an independent investigator in intracerebral hemorrhage (ICH) research. The applicant has shown a firm commitment to a biomedical research career and has acquired extensive training and expertise in molecular biology, histology, and animal models of ICH. He believes that enhancing his expertise in these areas and persuing additional training in in vitro experimentation and cellular neurobiology will improve his competitiveness. His mentor, Dr, Sylvain Dore, is an established neuroscientist in the areas of prostaglandin (PG) receptors, ischemic stroke, and aging, with expertise in primary cell cultures and cellular and molecular neurobiologic approaches. Dr. Solomon H. Snyderwill serve as an internal collaborator, while Drs. Eng H. Lo and Gary A. Rosenberg will serve as the consultants. They will provide him both intellectual and technical advice in their fields of expertise. The goal of this research is to understand the role of PGE2 receptors in the aging brain after ICH. We hypothesize that PGE2 EP1 and EPS receptors promote acute brain injury, whereas EP2 and EP4 receptors promote neuroprotection after ICH. Three specific aims will test our hypothesis. 1) Determine whether the PGE2 EP1 and EPS receptors increase brain injury in in vivo models of ICH, assess whether brain injury is accentuated in aged animals vs young ones, and assess the MMP-9 role; 2) Determine whether the PGE2 EP2 and EP4 receptors attenuate brain injury in in vivo models of ICH, assess the effect of aging on ICH outcomes, and assess the MMP-9 role; 3) Determine the effects of PGE2 EP1-4 receptor activation and inhibition on neuronal survival in in vitro models of heme-induced toxicity and assess the MMP-9 role. We will use the two mouse ICH models in our lab and our available EP receptor knockout C57BL/6 mice. Pharmacologic approaches (selective agonists and antagonists) for each of the receptors will be used to corroborate those findings from the knockouts. We believe that this work will provide a better understanding of specific PGE2 receptor functions in the aging brain after ICH. The data generated from this study will be strong enough to support the candidate's submission of an independent NIH R01 grant. RELEVANCE (See instructions): The work proposed will provide a better understanding of specific prostaglandin E2 receptor functions in the aging brain after intracerebral hemorrhage. Insight into these receptors may contribute to the basis for therapeutic intervention for intracerebral hemorrhage in the elderly.