Endogenous circadian clocks regulate NG2-glia regenerative potential

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PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of death and disability in patients aged 1-44 years. While there is no treatment for TBI, one potential strategy is to harness the brain’s native capacity for cellular regeneration to replace lost cells. NG2-glia, the largest population of regenerative cells in the adult CNS, can proliferate and differentiate into multiple glial cell types; uncovering the molecular pathways regulating these NG2-glia processes is a key step to develop future therapies for TBI. The candidate previously found that cortical NG2- glia are regulated by the molecular circadian clock, a well-characterized 24-hr transcriptional-translational feedback loop, with a key contribution by the clock gene Bmal1. However, the mechanism by which the clock affects regenerative potential as well as the generalizability of this mechanism to other NG2-glia (e.g. white matter NG2-glia) are unknown. In this proposal, the candidate hypothesizes that the NG2-glia endogenous circadian clock directly governs molecular pathways to regulate regenerative potential, both in health and disease. He will test this hypothesis with the following aims: 1) Determine the clock-dependence of cortical and white matter NG2-glia proliferation and differentiation in the healthy brain and in response to TBI; 2) Identify the clock-dependent molecular programs regulating cortical NG2-glia proliferation in the healthy and injured brain; 3) Define the differential expression of BMAL1 target genes during basal and injury-induced cortical NG2-glia proliferation. Successful completion of these aims will identify the clock-dependent molecular pathways underlying NG2-glia regenerative potential that will serve as future targets to manipulate post-TBI cellular regeneration. Currently holding positions as Attending Physician in Critical Care Medicine at Children’s National Hospital and Assistant Professor of Pediatrics at George Washington University School of Medicine and Health Sciences, the candidate is committed to a career in academic medicine. With >75% protected time, as supported by his institution, the candidate will be guided by his primary mentor (Vittorio Gallo) and co-mentors (Kazue Hashimoto-Torii, Amita Sehgal, Regina Armstrong). He has access to laboratory space, supplies, and research funding to carry out the proposed project. His career development plan is comprised of hands-on training and didactics to accomplish his training goals, which includes technical and non-technical skills necessary for future independence. From a technical aspect, he seeks training in in vitro techniques, human post-mortem tissue evaluation, and omics sciences; there is a focus on the last, as his proposal uses translatomics and chromatin mapping, two approaches ideally suited for investigating the changes in NG2-glia molecular programs induced by the transcription factors comprising the circadian clock. Completion of his training plan will permit the candidate to conduct studies on a variety of scales, allowing him to fulfill the “bench to bedside” mantra that motivates him to tread the path of a physician scientist. Furthermore, he will have positioned himself as an investigator at a unique intersection of circadian rhythms, neurotrauma, and regenerative medicine.