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.

项目摘要/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。那里不接受TBI的治疗，一种潜在的策略是利用大脑的细胞再生能力取代丢失的细胞。 NG2-GLIA是成年中枢神经系统中最大的再生细胞群，可以增殖，并且分化为多种神经胶质细胞类型；发现调节这些NG2-GLIA的分子途径过程是开发TBI未来疗法的关键步骤。候选人先前发现皮质Ng2- 神经胶质由分子昼夜节律调节，这是一种良好的24小时转录转录反馈循环，具有时钟基因BMAL1的关键贡献。但是，时钟的机制影响这种机制对其他NG2-GLIA的再生潜力以及概括性（例如白色物质ng2-glia）是未知的。在此提案中，候选人假设NG2-GLIA内生昼夜节律的时钟直接控制了分子途径，以调节健康和疾病。他将以以下目的检验这一假设：1）确定皮质和白质NG2-GLIA增殖和健康大脑的分化以及对TBI的反应； 2）确定依赖于时钟的分子程序在健康和受伤的大脑中恢复皮质NG2-GLIA的增殖； 3）在基本和损伤诱导的皮质NG2-GLIA期间定义BMAL1靶基因的差异表达增殖。这些目标的成功完成将确定依赖于时钟的分子途径潜在的NG2-GLIA再生潜力将作为操纵TBI细胞后的未来目标再生。目前担任儿童国家重症监护医学医生的职位乔治华盛顿大学医学与健康学院的医院和助理教授科学，候选人致力于从事学术医学的职业。受支持的时间> 75％的保护时间在他的机构中，候选人将以他的主要心理（维托里奥·加洛）和联合给予（Kazue）为指导。 Regina Armstrong的Amita Sehgal Hashimoto-Torii）。他可以使用实验室空间，供应和研究资金来执行拟议项目。他的职业发展计划完成了动手培训和完成他的培训目标的教学法包括未来所需的技术和非技术技能独立。从技术方面，他寻求体外技术培训，人类验尸组织评估和ODICS科学；最后一个重点映射，非常适合研究NG2-GLIA分子程序的变化的两种方法通过完成昼夜节律的转录因子。完成他的培训计划将允许候选人对各种尺度进行研究，使他能够实现“卧床卧床的”咒语激励他踏上身体科学家的道路。此外，他将把自己定位为在昼夜节律，神经曲和再生医学的独特交集中的研究者。