Endogenous circadian clocks regulate NG2-glia regenerative potential

内源性生物钟调节 NG2 神经胶质细胞的再生潜力

• 批准号: 10807543
• 负责人: Terry Dean
• 金额: $ 18.24万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-26 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807543
• 关键词: ARNTL gene; Address; Adult; Affect; Affinity Chromatography; American; Autopsy; Binding; Brain; Brain Injuries; CSPG4 gene; Cause of Death; Cells; Child; Chromatin; Chronobiology; Circadian Rhythms; Code; Collaborations; Critical Care; DNA Binding; DNA-Protein Interaction; Data; Deoxyuridine; Dependence; Development; Development Plans; Developmental Biology; Disease; Educational process of instructing; Epidemic; Evaluation; Feedback; Foundations; Funding; Future; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Goals; Head; Health; Health Sciences; Heterogeneity; Hospitals; Human; Immunohistochemistry; In Vitro; Injury; Institution; Laboratories; Maps; Measures; Medicine; Mentors; Methods; Molecular; Mus; Natural regeneration; Nervous System Trauma; Neuroglia; Neurosciences; Pathology; Pathway interactions; Patients; Pediatrics; Periodicity; Persons; Phase; Physicians; Population; Positioning Attribute; Process; Proliferating; Property; Proteins; Public Health; Publishing; Regenerative Medicine; Reporting; Research; Research Personnel; Rest; Ribosomes; Role; Science; Scientist; System; TBI treatment; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transgenic Organisms; Translating; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; Universities; Washington; Writing; aged; bench to bedside; career; career development; cell regeneration; cell type; circadian; circadian biology; circadian pacemaker; clinically relevant; conditional knockout; cost; differential expression; disability; experience; medical schools; mouse model; pre-clinical research; professor; programs; regeneration following injury; regeneration potential; regenerative; regenerative cell; regenerative therapy; response; skills; targeted treatment; therapy development; transcription factor; transcriptome sequencing; translatome; white matter

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.

项目摘要/摘要 创伤性脑损伤是1-44岁患者死亡和致残的主要原因。在那里的时候 不能治疗脑外伤，一个潜在的策略是利用大脑固有的细胞再生能力 以取代丢失的细胞。NG2-胶质细胞是成人中枢神经系统中最大的再生细胞群，它可以增殖和 分化为多种神经胶质细胞类型；揭示调节NG2-神经胶质细胞的分子途径 过程是开发未来脑外伤治疗方法的关键一步。候选人之前发现大脑皮层NG2- 神经胶质细胞受分子昼夜节律时钟的调节，这是一种具有24小时转录-翻译特征的生物钟。 反馈环路，其中时钟基因BMal1起到了关键作用。然而，时钟所用的机制 影响再生潜力以及这一机制对其他NG2-胶质细胞(如白色)的普适性 物质NG2-胶质)是未知的。在这项提议中，候选人假设NG2-胶质细胞内源性 生物钟直接控制分子途径来调节再生潜力，无论在健康还是在 疾病。他将通过以下目的来检验这一假说：1)确定大脑皮层和大脑皮质的时钟依赖性 脑白质NG2-胶质细胞的增殖和分化及对脑损伤的反应；2)鉴定 时钟依赖的分子程序调节健康和损伤大脑皮质NG2-神经胶质细胞的增殖； 3)明确BMAL1靶基因在基础和损伤诱导的皮质NG2胶质细胞中的差异表达 扩散。这些目标的成功完成将识别依赖时钟的分子通路 潜在的NG2-神经胶质细胞再生潜力将成为未来操纵脑损伤后细胞的靶点 再生。目前在国立儿童医院担任重症监护医学主治医生 乔治·华盛顿大学医学与健康学院儿科助理教授 作为一名理科学生，这位候选人致力于学术医学的职业生涯。受支持的受保护时间为&gt；75% 在他的学校，候选人将由他的主要导师(维托里奥·加洛)和共同导师(Kazue)指导 桥本-鸟井、阿米塔·塞格尔、里贾娜·阿姆斯特朗)。他有权使用实验室空间、用品和研究 为实施拟议的项目提供资金。他的职业发展计划包括实践培训和 完成他的训练目标的教学，其中包括未来所需的技术和非技术技能 独立。在技术方面，他寻求体外技术方面的培训，即人类死后组织 评估和组学；重点放在最后一项上，因为他的提案使用了翻译组学和染色质 作图，两种非常适合研究NG2-胶质细胞分子程序变化的方法 由组成生物钟的转录因子决定。他的训练计划的完成将使 候选人在不同的尺度上进行研究，使他能够实现“从板凳到床边”的咒语 激励他走上内科科学家的道路。此外，他将把自己定位为一个 在昼夜节律、神经创伤和再生医学的独特交叉点上的研究者。