Prostaglandin signaling following seizures

我的职业目标是成为一名独立而成功的科学家，致力于了解脑损伤的细胞和分子机制，并最终开发新的治疗策略。作为一名博士后研究员，我想通过专注于癫痫等重大神经疾病来研究神经炎症和神经退行性变，这导致我在丁莱丁博士的实验室进行博士后培训。到目前为止，我的主要研究重点是了解前列腺素信号如何在癫痫发作期间和之后调节慢性脑部炎症和变性。我们一直在进行两个主要的研究途径：1)开发选择性修饰前列腺素受体EP2的小分子；2)确定这些化合物如何影响癫痫小鼠模型的病理。我们已经朝着这两个目标取得了重大进展，并开发了新型选择性变构增强剂和EP2受体拮抗剂。最近，我们发现，在匹罗卡品诱导的小鼠癫痫持续状态后，药物抑制EP2受体提供了许多有益的效果，包括减少死亡率、体重减轻、功能丧失、神经炎症和神经变性。我们还证明了EP2受体可能通过cAMP/EPAC信号调节小胶质细胞中多种致炎基因的表达。目前的K99/R00研究方案侧重于扩展这些发现，通过利用这组新发现的拮抗剂和两个条件基因敲除小鼠品系来更完整地了解前列腺素信号在癫痫发作后的神经发病机制中的作用，在这两个品系中，EP2受体在前脑神经元或小胶质细胞/巨噬细胞中被消融。这些研究的成功完成将为癫痫脑中炎症和损伤的调节提供新的见解，这应该与许多其他急性和慢性神经退行性疾病相关，包括中风、多发性硬化症和阿尔茨海默病。因此，这项研究可以为开发治疗这些疾病的新疗法提供指导。埃默里大学的研究环境相当友好、包容和合作。我的专业知识和经验使我准备好领导这个拟议的项目，我的导师(Raymond Dingledine博士和James McNamara博士)将在癫痫模型、神经病理学、行为神经科学以及项目管理方面的指导(如人员配备、监管问题和预算)方面提供指导、培训和监督。我还将接受克里·雷斯勒博士关于慢病毒介导的小鼠海马体RNA干扰的培训，参加高级神经科学技术、研究伦理和实验室管理方面的课程，并参加科学会议。总体而言，我的建议与NIH独立之路奖的目标非常相关，因为它提供了技术和管理培训，建立了我自己的研究项目，使我能够从NIH寻求资金，并最终促进我向独立调查人员的转变。

DESCRIPTION (provided by applicant): My career goal is to be an independent and successful scientist dedicated to understanding the cellular and molecular mechanisms of brain injuries, and ultimately developing novel therapeutic strategies. As a postdoctoral fellow, I wanted to study neuroinflammation and neurodegeneration by focusing on a major neurological disorder such as epilepsy, which led me to pursue postdoctoral training in Dr. Dingledine's laboratory. Up to now my major research focus has been to understand how prostaglandin signaling regulates chronic brain inflammation and degeneration during and after seizures. We have pursued two major avenues of research 1) to develop small molecules that selectively modify prostaglandin receptor EP2, and 2) to determine how these compounds affect the pathologies in mouse models of epilepsy. We have made significant progress toward both goals and have developed novel selective allosteric potentiators and antagonists for EP2 receptor. More recently, we have found that pharmacological inhibition of EP2 receptors after pilocarpine-induced status epilepticus in mice provides many beneficial effects including reductions in mortality, weight loss, functional loss, neuroinflammation and neurodegeneration. We also demonstrated that EP2 receptors regulate expression of a variety of pro-inflammatory genes in microglia likely via cAMP/Epac signaling. The current K99/R00 research proposal focuses on extending these findings to provide a more complete understanding of prostaglandin signaling in the neuropathogenesis following seizures, by taking advantage of this newly identified group of antagonists together with two conditional knockout mouse strains in which EP2 receptors are ablated either in forebrain neurons or microglia/macrophages. Successful completion of these studies will provide new insights on the regulation of inflammation and injury in epileptic brain that should be relevant to many other acute and chronic neurodegenerative disorders involving neuroinflammation with EP2 activation, including stroke, multiple sclerosis and Alzheimer's disease. Thus, this research could provide guidance to develop novel therapies for the treatment of those diseases. The research environment at Emory University is quite friendly, accommodating and collaborative. My expertise and experiences have prepared me to lead the proposed project, and my mentors (Dr. Raymond Dingledine and Dr. James McNamara) will provide mentoring, training, and oversight in epilepsy models, neuropathology, behavioral neuroscience, and guidance in project administration (e.g. staffing, regulatory issues and budget). I will also receive training from Dr. Kerry Ressler for lentiviral-mediated RNA interference in the mouse hippocampus, take courses on advanced neuroscience techniques, research ethics and lab management, and participate in scientific meetings. Overall, my proposal is very relevant to the goals of the NIH Pathway to Independence Award by providing technical and administrative training, establishing my own research projects, allowing me to pursue funding from the NIH, and ultimately facilitating my transition to an independent investigator.