Role of PGE2 receptors in the aging brain after intracerebral hemorrhage

描述(由申请者提供)：该K01奖项的长期目标是为申请者在脑出血(ICH)研究中作为一名独立研究员的职业生涯做好准备。申请者表现出对生物医学研究事业的坚定承诺，并在分子生物学、组织学和脑出血动物模型方面获得了广泛的培训和专业知识。他认为，提高自己在这些领域的专业知识，并争取在体外实验和细胞神经生物学方面进行额外的培训，将提高他的竞争力。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拥有专业知识。所罗门·施奈德博士将担任内部合作者，罗英豪博士和加里·A·罗森伯格博士将担任顾问。他们将在他们的专业领域为他提供智力和技术方面的建议。本研究的目的是了解PGE2受体在脑出血后脑老化中的作用。我们假设PGE2EP1和EPS受体促进急性脑损伤，而EP2和EP4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)确定在体脑出血模型中PGE2 EP1和EPS受体是否增加了脑损伤，评估了老年动物与年轻动物相比脑损伤是否加重，并评估了MMP-9的作用；2)确定PGE2 EP2和EP4受体是否减轻了在体脑出血模型中的脑损伤，评估了衰老对脑出血预后的影响，并评估了MMP-9的作用；3)确定了PGE2 EP1-4受体的激活和抑制对体外血红素诱导毒性模型神经元存活的影响，并评估了MMP-9的作用。我们将使用我们实验室中的两个小鼠脑出血模型和我们可用的EP受体基因敲除C57BL/6小鼠。每种受体的药理学方法(选择性激动剂和拮抗剂)将被用来证实从基因敲除中得到的那些发现。我们相信，这项工作将为更好地了解脑出血后衰老大脑中特定的PGE2受体功能。这项研究产生的数据将足以支持候选人提交独立的NIH R01拨款。相关性(见说明书)：建议的工作将提供更好的了解脑出血后老化的脑中前列腺素E2受体的特定功能。对这些受体的了解可能有助于老年脑出血的治疗干预。

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.