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.

摘要 大脑是由神经元和非神经元之间复杂的相互作用网络构成的。 神经胶质细胞神经胶质细胞在脑发育和功能中起着积极和重要的作用， 功能障碍越来越多地与神经障碍有关。然而，我们仍然有一个 令人惊讶的是，对大多数神经胶质细胞类型的基础生物学的理解有限， 神经胶质细胞串扰对正常脑功能的重要性。在大脑中尤其如此 白色物质，占人脑体积的一半， 任何大脑区域的神经胶质与神经元的比例。近年来，单细胞测序的进展 能够详细研究灰质神经元和神经胶质的分子和功能特性， 物质脑区域。不幸的是，大量的技术障碍目前阻碍了我们的能力， 研究大脑白色物质和白色物质神经胶质细胞在相同的细节水平。所以我们 对白色物质的分子和功能特性的理解落后于灰色物质 这对我们理解健康的大脑发育构成了重大障碍， 功能和我们治疗神经系统疾病的能力。为了克服这些技术和 为了克服科学障碍，我的实验室将联合收割机结合基于邻近的体内定量蛋白质组学和新的 病毒工具来定义大脑白色物质的分子景观， 细胞和亚细胞特异性。我们将在健康的小鼠中进行这些实验 在不同的发育时间点，以及在建立的疾病模型， 脑病理学主要由白色物质功能障碍驱动。最终，我们将应用这一点 蛋白质组学数据研究胶质-神经元和胶质-胶质细胞的特定分子机制 脑发育和疾病期间脑白色物质中的串扰，特别关注 两种胶质细胞类型的相互作用：星形胶质细胞和少突胶质细胞。这些实验将 为我们了解大脑白色物质的分子结构提供了前所未有的窗口， 解决了我们对大脑一半如何发育，功能， 并且受到疾病的影响。