Astrocyte Transcriptional Dependencies in Brain Circuits

脑回路中星形胶质细胞的转录依赖性

• 批准号: 10665221
• 负责人: Benjamin Deneen
• 金额: $ 76.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665221
• 关键词: Adult; Alzheimer' s Disease; Astrocytes; Brain; Cells; Dependence; Development; Disease; Exhibits; Family; Family Study; Functional disorder; Genes; Genetic Transcription; Hippocampus; Knowledge; Link; Maps; Molecular; NFIA gene; Neurodegenerative Disorders; Neurons; Pathogenesis; Physiological; Play; Property; Proteomics; Renaissance; Role; aging brain; epigenomics; member; mouse model; nervous system disorder; nuclear factor 1; olfactory bulb; transcription factor; transcriptomics

Project Summary Over the past twenty years our knowledge of astrocytes has undergone a renaissance highlighted by the identification of dynamic physiological activities, key roles in circuit function, and diverse molecular properties. Central to the physiological activities of every cell are transcription factors (TFs), yet roles for TFs in mature astrocyte function and associated circuits in the brain have remained relatively undefined. Our molecular studies on astrocyte diversity highlighted the expression of developmental TFs in mature astrocytes, in the adult brain. Among these TFs are members of the Nuclear Factor I (NFI)- and Sox- family, which play essential roles in early astrocyte development and continue to be expressed in a vast majority of mature astrocytes throughout the adult brain. Despite exhibiting universal expression in astrocytes across all regions, we found that NFIA and Sox9 exhibit region specific roles in mature astrocytes, where hippocampal astrocytes require NFIA to maintain their functional integrity, while olfactory bulb astrocytes require Sox9. Our finding that astrocytes exhibit region specific transcriptional dependencies, where at given TF is absolutely essential for function in one region, but is dispensable in other regions, serves as the foundational observation for this R35 application. We will use other NFI- and Sox- family TF members that are universally expressed in astrocytes to map region-specific transcriptional dependencies across the developing, adult, and aging brain. Our analysis will be comprehensive, spanning core astrocyte functions, interactions with neurons, and circuit-level activities. We posit that these region-specific transcriptional dependencies for astrocyte function will provide an entry point for understanding how astrocyte diversity is encoded. Therefore, we will use a host of transcriptomic, epigenomic, and proteomic approaches to uncover how these regional-specific TF functions are conferred, while functionalizing roles for key downstream target genes. Finally, astrocyte dysfunction is associated with a host of neurodegenerative diseases, including Alzheimer’s Disease. Here, we will apply our findings and new mouse models to AD, seeking to uncover how these core features of astrocyte TF function contribute to AD disease pathogenesis.

项目概要 在过去的二十年里，我们对星形胶质细胞的了解经历了一次复兴，其突出表现是 识别动态生理活动、电路功能中的关键作用以及不同的分子特性。 每个细胞生理活动的核心是转录因子 (TF)，但 TF 在成熟细胞中的作用 星形胶质细胞的功能和大脑中的相关回路仍然相对不明确。我们的分子 星形胶质细胞多样性的研究强调了成熟星形胶质细胞中发育性转录因子的表达， 成人的大脑。这些 TF 包括核因子 I (NFI) 和 Sox 家族的成员，它们发挥着重要作用 在早期星形胶质细胞发育中发挥作用，并继续在绝大多数成熟星形胶质细胞中表达 整个成人大脑。尽管在所有区域的星形胶质细胞中都表现出普遍表达，但我们发现 NFIA 和 Sox9 在成熟星形胶质细胞中表现出区域特异性作用，而海马星形胶质细胞需要 NFIA 维持其功能完整性，而嗅球星形胶质细胞则需要 Sox9。 我们发现星形胶质细胞表现出区域特异性转录依赖性，其中在给定的 TF 下 对于一个地区的功能来说绝对必要，但在其他地区则可有可无，作为基础 对此 R35 应用的观察。我们将使用其他 NFI 和 Sox 家族 TF 成员，这些成员都是通用的 在星形胶质细胞中表达，以绘制发育中、成人和发育阶段的区域特异性转录依赖性。 老化的大脑。我们的分析将是全面的，涵盖星形胶质细胞的核心功能、与神经元的相互作用、 和电路级活动。我们假设星形胶质细胞的这些区域特异性转录依赖性 函数将为理解星形胶质细胞多样性如何编码提供一个切入点。因此，我们将使用 一系列转录组学、表观基因组学和蛋白质组学方法来揭示这些区域特异性转录因子如何 赋予功能，同时功能化关键下游靶基因的作用。最后是星形胶质细胞 功能障碍与许多神经退行性疾病有关，包括阿尔茨海默病。在这里，我们 将把我们的发现和新的小鼠模型应用于 AD，试图揭示星形胶质细胞的这些核心特征如何 TF 功能有助于 AD 疾病的发病机制。