Molecular determinants of oligodendrocyte differentiation and myelination

少突胶质细胞分化和髓鞘形成的分子决定因素

• 批准号: RGPIN-2020-06521
• 负责人: Furber, Kendra
• 金额: $ 2.19万
• 依托单位: University of Northern British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761487
• 关键词: Molecular; determinants; oligodendrocyte; differentiation; myelination

Oligodendrocytes are the myelinating glia of the central nervous system. These cells extend numerous processes that wrap the neuronal axons in a compact membranous sheath. The myelin sheath allows for fast, efficient neurotransmission, which is important for both coordinated movement and higher cognitive functions. Early postnatal development is the most intense period of myelination in the brain. During this time, stem cells undergo changes through several distinct stages, migrating throughout the cortex and underlying white matter to reach a mature, myelinating phenotype. Progress through these stages is governed by transcriptional networks regulating gene expression. While our knowledge of individual transcription factors that are involved in oligodendrogenesis continues to expand, ultimately these need to be considered in the context of a broader regulatory network. Several epigenetic modifiers, including histone acetyltransferases (HATs) and histone deacetylases (HDACs), modulate the accessibility of chromatin to regulate transcription. My long-term vision for a NSERC-funded research program is to define the molecular players and interaction networks that regulate developmental myelination. In this initial research proposal, my team will work to systematically define the role of HATs and HDACs in the proliferation and differentiation of oligodendrocyte progenitor cells. We will characterize the expression levels and subcellular location of acetyltransferases and deacetylases during each stage of differentiation to determine key regulators of oligodendrogenesis. Integrated genomic and proteomic approaches will be employed to identify transcriptional complexes regulating gene expression providing a rigorous, cutting-edge training environment for undergraduate and graduate students. The emerging role of acetyltransferases and deacetylases, both through modification of histones and other target proteins (including transcription factors), signifies the importance of these post-translational modifications in regulating cellular function. Relatively little is known regarding the specific roles of many of these enzymes in cell differentiation, such as how they are targeted to different regions of the genome and the extent of overlap of function between the different classes. Thus, my research program will contribute to the fundamental understanding of how the coordinated actions of transcription factors and epigenetic modifiers lead to the highly orchestrated and tightly regulated gene expression in the developing brain.

少突胶质细胞是中枢神经系统的髓鞘形成胶质细胞。这些细胞延伸出许多突起，将神经元轴突包裹在致密的膜鞘中。髓鞘允许快速，有效的神经传递，这对协调运动和更高的认知功能都很重要。出生后早期发育是大脑中髓鞘形成最强烈的时期。在此期间，干细胞经历了几个不同阶段的变化，在整个皮层和下面的白色物质中迁移，以达到成熟的髓鞘形成表型。通过这些阶段的进展是由调控基因表达的转录网络控制的。虽然我们对参与少突胶质细胞发生的单个转录因子的了解不断扩大，但最终这些需要在更广泛的调控网络中加以考虑。几种表观遗传修饰剂，包括组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC），调节染色质的可及性以调节转录。我对NSERC资助的研究项目的长期愿景是定义调节发育髓鞘形成的分子参与者和相互作用网络。在这个初步的研究计划中，我的团队将系统地确定HAT和HDAC在少突胶质细胞祖细胞增殖和分化中的作用。我们将在分化的每个阶段表征乙酰转移酶和脱乙酰酶的表达水平和亚细胞位置，以确定少突分化的关键调节因子。综合基因组学和蛋白质组学的方法将被用来确定调节基因表达的转录复合物，为本科生和研究生提供一个严格的，前沿的培训环境。乙酰转移酶和脱乙酰酶通过修饰组蛋白和其他靶蛋白（包括转录因子）而发挥的作用表明这些翻译后修饰在调节细胞功能中的重要性。关于这些酶中的许多在细胞分化中的具体作用，例如它们如何靶向基因组的不同区域以及不同类别之间的功能重叠程度，相对知之甚少。因此，我的研究计划将有助于从根本上理解转录因子和表观遗传修饰剂的协调作用如何导致发育中大脑中高度协调和严格调控的基因表达。