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

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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.