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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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。无法治疗 TBI，一种潜在的策略是利用大脑的细胞再生能力 NG2-神经胶质细胞是成人中枢神经系统中最大的再生细胞群，可以替代丢失的细胞。分化成多种神经胶质细胞类型；揭示调节这些 NG2-神经胶质细胞的分子途径该候选人之前发现皮质 NG2- 是开发未来 TBI 疗法的关键一步。神经胶质细胞受分子生物钟的调节，分子生物钟是一种明确的 24 小时转录-翻译时钟反馈环路，其中时钟基因 Bmal1 做出了关键贡献。影响再生潜力以及该机制对其他 NG2 神经胶质细胞（例如白色 NG2-glia）未知。在该提案中，候选者认为 NG2-glia 是内源性的。生物钟直接控制分子途径来调节健康和再生潜力他将通过以下目标来检验这一假设：1）确定皮质和神经元的时钟依赖性。健康大脑中的白质 NG2-神经胶质细胞增殖和分化以及对 TBI 的反应 2) 识别时钟依赖性分子程序调节健康和受伤大脑中皮质 NG2-神经胶质细胞的增殖； 3)定义BMAL1靶基因在基底和损伤诱导的皮质NG2-胶质细胞过程中的差异表达成功完成这些目标将确定时钟依赖性分子途径。 NG2-神经胶质细胞潜在的再生潜力将作为未来操纵 TBI 后细胞的目标目前担任国家儿童医院重症监护医学主治医师。乔治华盛顿大学医学与健康学院医院和儿科助理教授科学，候选人致力于学术医学事业，受支持的保护时间超过 75%。根据他的机构，候选人将受到他的主要导师（Vittorio Gallo）和共同导师（Kazue）的指导 Hashimoto-Torii、Amita Sehgal、Regina Armstrong）他可以使用实验室空间、用品和研究。他的职业发展计划包括实践培训和实施拟议项目的资金。实现培训目标的教学方法，包括未来所需的技术和非技术技能从技术方面来说，他寻求体外技术、人体死后组织方面的培训。评估和组学科学；重点是最后一个，因为他的提案使用了翻译组学和染色质映射，两种方法非常适合研究 NG2-胶质细胞分子程序诱导的变化通过构成生物钟的转录因子，完成他的训练计划将允许候选人进行各种规模的研究，使他能够履行“从实验室到临床”的口号此外，他还将自己定位为一名医学科学家。昼夜节律、神经创伤和再生医学的独特交叉点的研究者。