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: 10390425
• 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/10390425
• 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; gene network; 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.

总结 星形胶质细胞是中枢神经系统中数量最多的胶质细胞，在中枢神经系统的各个方面都起着重要的作用。 大脑生理学的方方面面我们实验室最近的研究确定了五种分子和 脑中功能不同的星形胶质细胞亚群。其中一个亚群是 由细胞表面标记物CD 51特异性标记，并被赋予增强的 突触发生功能，使我们假设CD 51+星形胶质细胞发挥重要作用 大脑回路的运作。为了确定CD 51+星形胶质细胞如何促进回路功能， 我们建立了一个CD 51-FLP小鼠系，使我们能够选择性地标记和操纵这一点， 星形胶质细胞的数量。解读调节CD 51+的机制 在星形胶质细胞中，我们发现转录因子Sox 9在该亚群中富集。 在一个新产生的小鼠系中的初步研究，该小鼠系特异性消除了Sox 9， 星形胶质细胞显示，这种转录因子选择性地调节星形胶质细胞的形态， 海马体和嗅球中的回路功能以衰老依赖的方式。在一起， 这些新的小鼠品系将使我们能够揭示CD 51+星形胶质细胞如何调节大脑回路， 揭示了Sox 9在衰老过程中控制星形胶质细胞多样性和功能的新作用。 根据这些初步意见的力度，我们提出以下建议 明确的目标。在具体目标1中，我们将定义解剖学，形态学和生理学 CD 51+和CD 51-星形胶质细胞在衰老大脑中的特性，并破译它们如何发挥作用 海马体和嗅球的电路功能。在具体目标2中，我们将使用 星形胶质细胞特异性Sox 9敲除小鼠，以破译它如何调节星形胶质细胞的功能， 老化的大脑以及星形胶质细胞的这些变化如何影响海马体的电路功能， 嗅球在具体目标3中，我们将确定Sox 9如何调节星形胶质细胞的多样性， 老化，并将我们的研究结果与Sox 9 ChIP-Seq结合，以破译Sox 9靶基因网络。