Defining Neurotherapeutic Targets in Hypoxia-Induced CHOP-10 Signaling Networks

描述(由申请人提供)： 这项提案的首要目标是开发预防中风后迟发性神经元丢失的治疗方法。哈特曼博士是一名神经学家和博士后研究员，对控制神经元在缺血和神经退化条件下存活的遗传机制感兴趣。候选人的长期目标是建立一个独立的、学术研究计划，实施方法学，以弥合临床前疾病建模和神经治疗发现过程之间的差距。在最初的两年时间里，哈特曼博士将接受有关细胞死亡信号机制、高含量筛选和小分子发现以及促进研究人员支持的基础研究发展为临床试验的过程的指导。拟议的职业发展计划将使候选人能够使用将小分子抑制剂或转基因细胞系与高含量图像分析相结合的新方法来定义神经元中低氧诱导的转录依赖死亡途径。此外，候选人将采用基于系统的生物信息学方法，使用体外中风模型构建、测试和完善关于疾病相关信号网络的假设。这些研究将主要在罗切斯特大学进行，匹兹堡大学的药物发现实验室将提供额外的资源。由罗切斯特临床转化科学研究所支持的教学经验和几个以技术为导向的短期课程丰富了培训计划。在接下来的三年独立阶段，候选人将：1)研究缺氧触发的bZIP转录反应网络中的细胞类型差异；2)确定控制CHOP-10‘S凋亡潜力的细胞信号和蛋白质-蛋白质相互作用；3)确定CHOP-10异二聚体因子c/eBP-β保护缺氧应激后神经元的机制。这些研究将检验中心假设，即CHOP-10和相关的异二聚体bZIP伙伴是中风后神经元存活的关键决定因素。 与公共卫生相关：治疗中风的治疗选择有限，需要在亚急性期支持濒危神经元存活的策略。该项目旨在确定中风后激活的遗传信号通路，并开发系统，以突出这种毁灭性疾病的新治疗方法。

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to develop therapies that protect against delayed neuron loss following stroke. Dr. Halterman is a neurologist and post-doctoral fellow interested in genetic mechanisms governing neuronal survival in ischemic and neurodegenerative conditions. The candidate's long-term objective is to establish an independent, academic research program that implements methodologies to bridge the gap between preclinical disease modeling and the neurotherapeutic discovery process. During the initial 2-year period, Dr. Halterman will receive mentoring in cell death signaling mechanisms, high-content screening and small molecule discovery, and processes to promote the development of investigator- supported basic research into clinical trials. The proposed career development plan will enable the candidate to define hypoxia-induced transcription-dependent death pathways in neurons using novel approaches that combine small molecule inhibitors or genetically modified cell lines with high-content image analysis. Moreover, the candidate will adopt approaches in systems-based bioinformatics, to construct, test and refine hypotheses regarding disease-relevant signaling networks using an in vitro stroke model. These studies will be carried out primarily at the University of Rochester, with additional resources made available by the Drug Discovery Laboratory at the University of Pittsburgh. Didactic experiences supported by the Rochester Clinical Translational Science Institute and several technique-oriented short courses enrich the training plan. During the subsequent 3-year independent phase, the candidate will: 1) investigate cell-type differences in the network of bZIP transcriptional responses triggered by hypoxia, 2) define the cell signaling and protein- protein interactions that govern CHOP-10's apoptotic potential, and 3) define the mechanism by which the CHOP-10 heterodimeric factor c/EBP-beta protects neurons after hypoxic stress. These studies will test the central hypothesis that CHOP-10 and related heterodimeric bZIP partners are critical determinants of neuron survival following stroke. RELEVANCE TO PUBLIC HEALTH: Therapeutic options for the treatment of stroke are limited, and strategies that support the survival of endangered neurons in the sub-acute period are needed. This project aims to identify genetic signaling pathways activated after stroke, and to develop systems that will highlight new treatments for this devastating condition.