Prostaglandin signaling following seizures

癫痫发作后的前列腺素信号传导

基本信息

批准号：
9281093
负责人：
Jianxiong Jiang
金额：
$ 5.9万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281093
关键词：
Ablation Acute Address Affect Alzheimer&apos s Disease Appearance Arrestins Astrocytes Award Behavioral Body Weight decreased Brain Brain Injuries Budgets Chronic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Dinoprostone Disease Encephalitis Environment Epilepsy Event Funding Genes Goals Hippocampus (Brain)Human Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Knockout Mice Laboratories Lead Mediating Mentors Microglia Modeling Modification Molecular Molecular Target Mouse Strains Multiple Sclerosis Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurodegenerative Disorders Neurons Neuropathogenesis Neurosciences PTGS2 gene Pathogenesis Pathologic Pathology Pathway interactions Pharmacology Phase Physiological Pilocarpine Play Postdoctoral Fellow Preparation Prosencephalon Prostaglandin Receptor Prostaglandins RNA Interference Reaction Receptor Activation Regulation Research Research Ethics Research Personnel Research Project Grants Research Proposals Rodent Model Role Scientist Seizures Series Signal Pathway Signal Transduction Source Status Epilepticus Stroke Synapses Techniques Testing Therapeutic Agents Training United States National Institutes of Health Universities Work base career cyclooxygenase 2 design drug discovery excitotoxicity experience functional loss innovation insight kainate knock-down lentiviral-mediated macrophage meetings mortality mouse model nervous system disorder neurogenesis neuroinflammation neuropathology neurotoxic neurotoxicity novel novel therapeutics oxidative damage post-doctoral training public health relevance receptor small molecule therapeutic target

项目摘要

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.

描述（由申请人提供）：我的职业目标是成为一名独立且成功的科学家，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，我想通过关注癫痫等主要神经系统疾病来研究神经炎症和神经变性，这促使我在 Dingledine 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调节癫痫发作期间和之后的慢性脑炎症和退化。我们进行了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小鼠癫痫模型的病理学。我们在这两个目标方面都取得了重大进展，并开发了针对 EP2 受体的新型选择性变构增强剂和拮抗剂。最近，我们发现在毛果芸香碱诱导小鼠癫痫持续状态后对 EP2 受体进行药理学抑制可产生许多有益效果，包括降低死亡率、体重减轻、功能丧失、神经炎症和神经变性。我们还证明 EP2 受体可能通过 cAMP/Epac 信号传导调节小胶质细胞中多种促炎基因的表达。当前的 K99/R00 研究计划侧重于扩展这些发现，通过利用这组新鉴定的拮抗剂以及两种 EP2 受体被消除的条件性敲除小鼠品系，更全面地了解癫痫发作后神经发病机制中的前列腺素信号传导在前脑神经元或小胶质细胞/巨噬细胞中。这些研究的成功完成将为癫痫大脑炎症和损伤的调节提供新的见解，这应该与许多其他涉及 EP2 激活神经炎症的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非常友好、包容和协作。我的专业知识和经验使我准备好领导拟议的项目，我的导师（Raymond Dingledine 博士和 James McNamara 博士）将提供癫痫模型、神经病理学、行为神经科学方面的指导、培训和监督，以及项目管理方面的指导（例如人员配置、监管问题和预算）。我还将接受 Kerry Ressler 博士关于小鼠海马慢病毒介导的 RNA 干扰的培训，学习先进神经科学技术、研究伦理和实验室管理的课程，并参加科学会议。总体而言，我的提案与 NIH 独立之路奖的目标非常相关，通过提供技术和行政培训、建立我自己的研究项目、允许我从 NIH 寻求资金，并最终促进我向独立研究者的过渡。