The facts of the matter: decoding the molecular properties of brain white matter using cell-type-specific quantitative proteomics

事实真相：使用细胞类型特异性定量蛋白质组学解码大脑白质的分子特性

• 批准号: 10685777
• 负责人: Katherine Therese Baldwin
• 金额: $ 137.75万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685777
• 关键词: Address; Architecture; Astrocytes; Biology; Brain; Brain Pathology; Brain region; Data; Development; Disease; Disease model; Functional disorder; Human; Mental disorders; Molecular; Mus; Neuroglia; Neurons; Oligodendroglia; Play; Property; Proteomics; Role; Specificity; Time; Viral; cell type; experimental study; gray matter; in vivo; nervous system disorder; novel; single cell sequencing; tool; white matter

Abstract The brain is built from an elaborate network of interactions between neurons and non-neuronal glial cells. Glial cells play active and essential roles in brain development and function, and glial dysfunction is increasingly implicated in neurological disorders. However, we still have a surprisingly limited understanding of the basic biology of most glial cell types and the importance of glial cell crosstalk for proper brain function. This is particularly true in the brain white matter, which comprises half of the volume of the human brain and possesses the highest glia-to-neuron ratio of any brain region. In recent years, advances in single cell sequencing have enabled a detailed study of the molecular and functional properties of neurons and glia in gray matter brain regions. Unfortunately, substantial technical barriers currently impede our ability to study the brain white matter and white matter glial cells at the same level of detail. Thus, our understanding of the molecular and functional properties of white matter lags behind that of gray matter, presenting a significant barrier to our understanding of healthy brain development and function and our ability to treat neurological disorders. To overcome these technical and scientific barriers, my lab will combine proximity-based in vivo quantitative proteomics with novel viral tools to define the molecular landscape of the brain white matter with regional, temporal, cellular, and subcellular specificity. We will perform these experiments in the healthy mouse brain at different developmental time points, as well as in established disease models where brain pathology is largely driven by white matter dysfunction. Ultimately, we will apply this proteomic data to investigate specific molecular mechanisms of glia-neuron and glia-glia crosstalk in brain white matter during brain development and disease, with a particular focus on the interaction of two glial cell types: astrocytes and oligodendrocytes. These experiments will provide an unprecedented window into the molecular architecture of the brain white matter and address several critical gaps in our understanding of how half of the brain develops, functions, and is impacted by disease.

抽象的 大脑是由神经元与非神经元之间相互作用的精心互动网络构建的 神经胶质细胞。神经胶质细胞在大脑发育和功能中起积极和重要作用，以及神经胶质 功能障碍越来越涉及神经系统疾病。但是，我们仍然有一个 出乎意料的有限的了解大多数神经胶质细胞类型的基本生物学和 神经胶质细胞串扰对于适当的大脑功能的重要性。在大脑中尤其如此 白质，其中包括人脑体积的一半，拥有最高 任何大脑区域的神经胶质与神经元比。近年来，单细胞测序的进展具有 能够详细研究神经元和粒神经胶质的分子和功能特性 物质大脑区域。不幸的是，目前实质性的技术障碍阻碍了我们的能力 在相同的细节水平上研究脑白质和白质细胞。因此，我们的 了解白质滞后的分子和功能特性的理解 物质，为我们对健康大脑发育的理解带来了重大障碍 功能和我们治疗神经系统疾病的能力。克服这些技术和 科学障碍，我的实验室将将基于近端的体内定量蛋白质组学与新颖 病毒工具以区域性，时间，时间为脑白质的分子景观 细胞和亚细胞特异性。我们将在健康鼠标中执行这些实验 大脑在不同的发育时间点以及既定的疾病模型中 脑病理学在很大程度上是由白质功能障碍驱动的。最终，我们将应用此 蛋白质组学数据以研究神经胶质神经元和神经胶质细胞的特定分子机制 在大脑发育和疾病期间，脑白质中的串扰，特别关注 两种神经胶质细胞类型的相互作用：星形胶质细胞和少突胶质细胞。这些实验会 提供一个前所未有的窗口，进入脑白质的分子结构， 在我们了解一半大脑，功能，功能， 并受到疾病的影响。