Endogenous circadian clocks regulate NG2-glia regenerative potential

项目总结/摘要 创伤性脑损伤（TBI）是1-44岁患者死亡和残疾的主要原因。虽然 目前还没有治疗创伤性脑损伤的方法，一个潜在的策略是利用大脑的细胞再生能力， 来替换丢失的细胞NG 2-神经胶质细胞是成年CNS中最大的再生细胞群体，可以增殖并分化为神经胶质细胞。 分化成多种神经胶质细胞类型;揭示调节这些NG 2-神经胶质细胞的分子途径 过程是开发TBI未来疗法的关键一步。该候选人先前发现，皮质NG 2- 神经胶质细胞受分子生物钟调节，分子生物钟是一种充分表征的24小时转录-翻译 反馈回路，与时钟基因Bmal 1的关键贡献。然而，时钟的机械装置 影响再生潜力以及该机制对其他NG 2-神经胶质细胞（例如白色 NG 2-神经胶质）未知。在该提案中，候选人假设NG 2-胶质细胞内源性 生物钟直接控制分子途径，以调节再生潜力，无论是在健康和 疾病他将测试这一假设与以下目标：1）确定时钟依赖性的皮质， 白色物质NG 2-健康脑中和响应于TBI的神经胶质细胞增殖和分化; 2）鉴定神经胶质细胞的增殖和分化。 调节健康和受损脑中皮质NG 2-胶质细胞增殖的时钟依赖性分子程序; 3)确定BMAL 1靶基因在基础和损伤诱导的皮质NG 2-胶质细胞中的差异表达 增殖这些目标的成功完成将确定生物钟依赖的分子通路 潜在的NG 2-胶质细胞再生潜力，将作为未来的目标，以操纵TBI后细胞 再生目前担任国家儿童医院重症监护医学主治医师 医院和乔治华盛顿大学医学与健康学院儿科助理教授 科学，候选人致力于学术医学事业。受保护时间>75%，如支持的 根据其所在机构，候选人将由其主要导师（Vittorio Gallo）和共同导师（Kazue Hashimoto-Torii，Amita Sehgal，Regina Armstrong）.他可以使用实验室的空间，用品和研究 为开展拟议项目提供资金。他的职业发展计划包括实践培训， 教学法，以实现他的培训目标，其中包括技术和非技术技能所需的未来 独立从技术方面来说，他寻求在体外技术方面的培训， 评估和组学科学;重点是最后一个，因为他的建议使用了翻译组学和染色质 映射，两种方法非常适合研究NG 2-胶质细胞分子程序诱导的变化 由构成生物钟的转录因子控制完成他的训练计划， 候选人进行各种规模的研究，使他能够履行“板凳到床边”的咒语， 促使他走上了医学科学家的道路。此外，他将自己定位为一个 研究人员在一个独特的交叉昼夜节律，神经创伤，和再生医学。

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.