Transcriptional control of OPC fate specification and homing to gray matter and white matter in the CNS

OPC命运规范的转录控制以及中枢神经系统灰质和白质的归巢

基本信息

批准号：
10588159
负责人：
Tou Yia Vue
金额：
$ 37.16万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588159
关键词：
ASCL1 gene Alleles Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Apical Area Astrocytes Axon BHLH Protein Basic Science Binding Sites Brain Cell Adhesion Molecules Cell Surface Proteins Cells Central Nervous System ChIP-seq Complex Corpus Callosum Demyelinating Diseases Demyelinations Development Disease Dorsal Electrophysiology (science)Electroporation Exhibits Fiber Functional disorder Generations Genes Genetic Genetic Techniques Genetic Transcription Genome Glioblastoma Glioma Goals Growth Factor Homing Immunoprecipitation Maintenance Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Mediating Messenger RNA Modeling Molecular Multiple Sclerosis Mus Myelin Myelin Basic Proteins Neoplasm Metastasis Nerve Degeneration Neuroglia Neurons Oligodendroglia Pathologic Play Population Process Proliferating Property Radial Regulation Reporting RiboTag Role Schizophrenia Specific qualifier value Surface System Testing Tetanus Helper Peptide Therapeutic Time Transcriptional Regulation Undifferentiated Ventricular axon guidance cell fate specification cell motility cell type combat conditional knockout constitutive expression contactin design differential expression experimental study glial cell development gliogenesis gray matter insight learned behavior mouse model mutant myelination neonatal brain nerve stem cell nervous system disorder neurogenesis novel oligodendrocyte precursor postnatal precursor cell progenitor programs protein expression response transcription factor transcriptome sequencing white matter

项目摘要

PROJECT SUMMARY Oligodendrocyte precursor cells (OPCs) are one the most proliferative and abundant cell types in the central nervous system (CNS). During development, OPCs widely dispersed into areas of gray matter or white matter, and readily differentiate to give rise to oligodendrocytes, which are responsible for insulating neuronal axons with myelin. Studies in mouse models have revealed that abnormal development of OPCs and oligodendrocytes is one of the underlying causes of neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and glioblastoma, the deadliest of brain cancers. Currently, it is unknown how OPCs are regulated to populate the gray matter (GM) or white matter (WM), and what mechanisms are responsible for selectively maintaining many OPCs in undifferentiated state while others mature into oligodendrocytes. Prior studies demonstrate that the transcription factor, ASCL1, is differentially expressed in OPCs, where it is relatively higher in WM-OPCs than in GM-OPCs. Experiments outlined in this proposal are designed to test the overall hypothesis that the level of ASCL1 specifies the fate of OPCs and determines their homing and properties in the GM or WM. To test this hypothesis, the proposed study will pursue the following specific aims. Specific Aim 1. To determine if a sustained high level of ASCL1 is responsible for specifying OPC fate and homing to WM over GM in the brain. Specific Aim 2. To identify functionally relevant genetic targets of ASCL1 specifically in OPCs using ChIP-seq and Ribo-Tag. Specific Aim 3. To determine if Cntn1, a novel target of ASCL1 that encodes for a cell surface protein, functions downstream of ASCL1 to mediate the homing of OPCs to the WM. Both ASCL1 and CNTN1 are essential for OPC development, proper myelination, and glioma progression and metastasis. We anticipate that completion of this study will offer new mechanistic insights into how OPC/oligodendrocyte related pathological conditions such as demyelination, neuronal degeneration, and cancers arise in the CNS, while at the same time also provide an entry point to potentially manipulate these cells for the treatment of these debilitating diseases.

项目概要少突胶质细胞前体细胞 (OPC) 是中枢神经系统中最具增殖性和最丰富的细胞类型之一。神经系统（CNS）。在发育过程中，OPC 广泛分散到灰质或白质区域，并容易分化产生少突胶质细胞，少突胶质细胞负责将神经元轴突与髓磷脂。对小鼠模型的研究表明，OPC 和少突胶质细胞的异常发育与神经系统疾病和病症（例如肌萎缩侧索硬化症（ALS））的根本原因之一，多发性硬化症（MS）和胶质母细胞瘤（最致命的脑癌）。目前，OPC 的作用尚不清楚调节以填充灰质 (GM) 或白质 (WM)，以及哪些机制负责选择性地将许多 OPC 维持在未分化状态，而另一些则成熟为少突胶质细胞。事先的研究表明，转录因子 ASCL1 在 OPC 中存在差异表达，其表达相对较弱。 WM-OPC 中的含量高于 GM-OPC 中的含量。本提案中概述的实验旨在测试整体假设 ASCL1 的水平指定 OPC 的命运并决定它们的归巢和 GM 或 WM 中的属性。为了检验这一假设，拟议的研究将追求以下具体目标。具体目标 1. 确定持续高水平的 ASCL1 是否与指定 OPC 命运有关大脑中向 WM 而非 GM 归巢。具体目标 2. 使用 ChIP-seq 识别 OPC 中 ASCL1 的功能相关遗传靶标和核糖核酸标签。具体目标 3. 确定 Cntn1（编码细胞表面蛋白的 ASCL1 新靶标）是否发挥作用 ASCL1 下游介导 OPC 归巢至 WM。 ASCL1 和 CNTN1 对于 OPC 发育、正常髓鞘形成和神经胶质瘤进展至关重要转移。我们预计这项研究的完成将提供新的机制见解 OPC/少突胶质细胞相关的病理状况，例如脱髓鞘、神经元变性和癌症发生在中枢神经系统，同时也提供了潜在操纵这些细胞的切入点用于治疗这些使人衰弱的疾病。