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 大脑是由神经元和非神经元之间相互作用的复杂网络构成的 胶质细胞。神经胶质细胞在大脑发育和功能中发挥着积极和重要的作用，神经胶质细胞 功能障碍越来越多地与神经系统疾病有关。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本生物学和 神经胶质细胞串扰对于大脑正常功能的重要性。这在大脑中尤其如此 白质占人脑体积的一半，具有最高的 任何大脑区域的胶质细胞与神经元的比率。近年来，单细胞测序技术取得了长足的进步。 能够详细研究灰色神经元和神经胶质细胞的分子和功能特性 物质大脑区域。不幸的是，目前巨大的技术障碍阻碍了我们的能力 以相同的细节水平研究大脑白质和白质神经胶质细胞。因此，我们的 对白质分子和功能特性的理解落后于对灰质的理解 问题，对我们理解健康的大脑发育和 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 科学障碍，我的实验室将把基于邻近的体内定量蛋白质组学与新颖的 病毒工具定义大脑白质的分子景观，包括区域、时间、 细胞和亚细胞特异性。我们将在健康小鼠身上进行这些实验 大脑在不同的发育时间点，以及在已建立的疾病模型中 大脑病理很大程度上是由白质功能障碍驱动的。最终，我们将应用这个 用于研究胶质细胞-神经元和胶质细胞-胶质细胞的特定分子机制的蛋白质组学数据 大脑发育和疾病期间大脑白质的串扰，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。这些实验将 为了解大脑白质的分子结构提供了前所未有的窗口 解决我们对大脑一半如何发育、运作的理解中的几个关键差距 并且受到疾病的影响。