Role of PGE2 receptors in the aging brain after intracerebral hemorrhage

描述（由申请人提供）：这个K 01奖的长期目标是准备申请人的职业生涯作为一个独立的研究人员在脑出血（ICH）研究。申请人对生物医学研究事业表现出坚定的承诺，并在分子生物学、组织学和ICH动物模型方面获得了广泛的培训和专业知识。他相信，提高自己在这些领域的专业知识，并在体外实验和细胞神经生物学方面进行额外的培训，将提高自己的竞争力。他的导师Sylvain Dore博士是前列腺素（PG）受体、缺血性中风和衰老领域的知名神经科学家，在原代细胞培养以及细胞和分子神经生物学方法方面具有专业知识。所罗门博士H.斯奈德将作为一个内部合作者，而工程师H。Lo和加里A.罗森伯格将担任顾问。他们将在各自的专业领域向他提供知识和技术咨询。本研究的目的是了解脑出血后PGE 2受体在脑老化中的作用。我们推测PGE 2、EP 1和EPS受体促进急性脑损伤，而EP 2和EP 4受体促进脑出血后的神经保护。三个具体目标将检验我们的假设。1)确定PGE 2 EP 1和EPS受体是否增加ICH体内模型中的脑损伤，评估老年动物与年轻动物相比脑损伤是否加重，并评估MMP-9的作用; 2）确定PGE 2 EP 2和EP 4受体是否减弱ICH体内模型中的脑损伤，评估衰老对ICH结果的影响，并评估MMP-9的作用; 3）在血红素诱导的毒性的体外模型中确定PGE 2 EP 1 -4受体激活和抑制对神经元存活的影响，并评估MMP-9的作用。我们将使用我们实验室的两种小鼠ICH模型和我们现有的EP受体敲除C57 BL/6小鼠。每种受体的药理学方法（选择性激动剂和拮抗剂）将用于证实敲除的结果。我们相信，这项工作将提供一个更好地了解特定的PGE 2受体功能的脑出血后，在老龄化的大脑。本研究产生的数据将足以支持候选人提交独立的NIH R 01资助。相关性（参见说明）：这项工作的提出将提供一个更好地了解特定的前列腺素E2受体功能的脑出血后，在老龄化的大脑。了解这些受体可能有助于老年人脑出血的治疗干预的基础。

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.