Defining Roles for Astrocyte Subpopulations in the Aging Brain

定义星形胶质细胞亚群在衰老大脑中的作用

• 批准号: 10192033
• 负责人: Benjamin Deneen
• 金额: $ 32.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10192033
• 关键词: Address; Affect; Aging; Alleles; Alzheimer' s Disease; Anatomy; Area; Astrocytes; Bacterial Artificial Chromosomes; Blood - brain barrier anatomy; Brain; Brain region; Cell surface; ChIP-seq; Coupled; Data; Disease; Evolution; Exhibits; Genes; Genetic; Genetic Transcription; Goals; Hippocampus (Brain); Knockout Mice; Label; Link; Metabolic; Molecular; Molecular Profiling; Morphology; Mus; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Pathologic; Physiological; Physiology; Play; Population; Property; Reporter; Role; age related; aging brain; base; genetic approach; in vivo; mouse model; nervous system disorder; neurotransmission; novel; olfactory bulb; prospective; response to injury; single-cell RNA sequencing; synaptogenesis; transcription factor; Address; Affect; Aging; Alleles; Alzheimer' s Disease; Anatomy; Area; Astrocytes; Bacterial Artificial Chromosomes; Blood - brain barrier anatomy; Brain; Brain region; Cell surface; ChIP-seq; Coupled; Data; Disease; Evolution; Exhibits; Genes; Genetic; Genetic Transcription; Goals; Hippocampus (Brain); Knockout Mice; Label; Link; Metabolic; Molecular; Molecular Profiling; Morphology; Mus; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Pathologic; Physiological; Physiology; Play; Population; Property; Reporter; Role; age related; aging brain; base; genetic approach; in vivo; mouse model; nervous system disorder; neurotransmission; novel; olfactory bulb; prospective; response to injury; single-cell RNA sequencing; synaptogenesis; transcription factor

Summary Astrocytes are the most abundant type of glial cell in the CNS and play vital roles in all facets of brain physiology. Recent studies from our lab identified five molecularly and functionally distinct astrocyte subpopulations in the brain. One of these subpopulations is specifically labeled by the cell surface maker CD51 and is endowed with enhanced synaptogenic function, leading us to hypothesize that CD51+ astrocytes play an important role in functioning brain circuits. To determine how CD51+ astrocytes contribute to circuit function, we created a CD51-FLP mouse line that allows us selectively label and manipulate this population of astrocytes in the brain. To decipher the mechanisms that regulate CD51+ astrocytes, we found that the transcription factor Sox9 is enriched in this subpopulation. Preliminary studies in a newly generated mouse line that specifically eliminates Sox9 in astrocytes revealed that this transcription factor selectively regulates astrocyte morphology and circuit function in the hippocampus and olfactory bulb in an aging-dependent manner. Together, these new mouse lines will enable us to uncover how CD51+ astrocytes regulate brain circuits and reveal novel roles for Sox9 in controlling astrocyte diversity and function during aging. Based on the strength of these preliminary observations, we propose the following specific aims. In specific aim 1, we will define the anatomical, morphological and physiological properties of CD51+ and CD51- astrocytes in the aging brain and decipher how they contribute to circuit function in the hippocampus and olfactory bulb. In specific aim 2, we will use our astrocyte-specific Sox9 knockout mouse to decipher how it regulates astrocyte function in the aging brain and how these changes in astrocytes impact circuit function in the hippocampus and olfactory bulb. In specific aim 3 we will determine how Sox9 regulates astrocyte diversity during aging and integrate our findings with Sox9 ChIP-Seq to decipher Sox9 target gene networks.

概括 星形胶质细胞是中枢神经系统中最丰富的胶质细胞类型，并且在所有人中起着至关重要的作用 大脑生理的方面。我们实验室的最新研究确定了五个分子， 大脑功能上不同的星形胶质细胞亚群。这些亚群之一是 由细胞表面制造商CD51特别标记，并具有增强 突触源功能，导致我们假设CD51+星形胶质细胞起着重要作用 在功能性的脑电路中。为了确定CD51+星形胶质细胞如何促进电路功能， 我们创建了一个CD51-FLP鼠标系列，该系列使我们有选择地标记并操纵此功能 大脑中星形胶质细胞的种群。破译调节CD51+的机制 星形胶质细胞，我们发现转录因子SOX9在该亚群中富含。 在新生成的小鼠系中的初步研究，该系列专门消除了Sox9 星形胶质细胞表明，该转录因子选择性调节星形胶质细胞形态和 以老化的方式在海马和嗅球中的电路功能。一起， 这些新的鼠标线将使我们能够发现CD51+星形胶质细胞如何调节脑电路 并揭示了Sox9在衰老过程中控制星形胶质细胞多样性和功能中的新作用。 根据这些初步观察的强度，我们提出以下内容 具体目标。在特定目标1中，我们将定义解剖学，形态学和生理学 CD51+和CD51-衰老大脑中星形胶质细胞的特性，并破译它们如何贡献 到海马和嗅球中的电路功能。在特定目标2中，我们将使用我们的 星形胶质细胞特异性SOX9基因敲除小鼠，以解读其调节星形胶质细胞功能 大脑衰老以及这些星形胶质细胞的变化如何影响海马和 嗅球。在特定目标3中，我们将确定Sox9如何调节星形胶质细胞多样性 衰老并将我们的发现与Sox9 Chip-Seq集成到破译Sox9目标基因网络。