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

• 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
• 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' 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

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.

项目摘要 少突胶质细胞前体细胞（OPC）是中央最增殖和丰富的细胞类型之一 神经系统（CNS）。在开发过程中，OPC广泛分散到灰质或白质区域， 并很容易区分以产生少突胶质细胞，该核细胞负责与神经元轴突绝缘 髓线。小鼠模型中的研究表明，OPC和少突胶质细胞的异常发育是 神经系统疾病和疾病的根本原因之一，例如肌萎缩性侧面硬化症（ALS）， 多发性硬化症（MS）和胶质母细胞瘤，是最致命的脑癌。目前，未知OPC是如何的 受监管以填充灰质（GM）或白质（WM），以及哪些机制负责 有选择地将许多OPC保持在未分化状态，而其他OPC则成熟到少突胶质细胞中。事先的 研究表明，转录因子ASCL1在OPC中差异表达，在该OPC中 在WM-OPC中，比GM-OPC高。该提案中概述的实验旨在测试整体 假设ASCL1的水平指定OPC的命运并确定其归巢和 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特定目标。 具体目标1。确定持续的高水平ASCL1是否负责指定OPC命运和 大脑中的通用汽车上的wm归寄给WM。 特定的目标2。使用芯片序列识别OPC中ASCL1的功能相关遗传靶标 和ribo-tag。 特定目的3。确定CNTN1是否是编码细胞表面蛋白的ASCL1的新型靶标，功能 ASCL1的下游介导OPC向WM的归纳。 ASCL1和CNTN1对于OPC发育，适当的髓鞘形成以及神经胶质瘤的进展以及 转移。我们预计这项研究的完成将为如何提供新的机械见解 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 癌症出现在中枢神经系统中，同时还提供了一个可能操纵这些细胞的切入点 治疗这些衰弱的疾病。