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

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神经胶质细胞类型，在所有细胞中发挥着至关重要的作用 大脑生理学的各个方面。我们实验室最近的研究确定了五种分子和 大脑中功能不同的星形胶质细胞亚群。这些亚群之一是 由细胞表面标记物 CD51 特异性标记，并被赋予增强的 突触发生功能，使我们推测 CD51+ 星形胶质细胞发挥重要作用 在功能性大脑回路中。为了确定 CD51+ 星形胶质细胞如何促进回路功能， 我们创建了一个 CD51-FLP 小鼠品系，允许我们选择性地标记和操纵它 大脑中的星形胶质细胞群。破译调节 CD51+ 的机制 星形胶质细胞中，我们发现转录因子 Sox9 在该亚群中富集。 对新生成的小鼠品系的初步研究，该小鼠品系特异性消除了 Sox9 星形胶质细胞显示该转录因子选择性调节星形胶质细胞形态 海马体和嗅球中的电路功能以衰老依赖性方式发挥作用。一起， 这些新的小鼠品系将使我们能够揭示 CD51+ 星形胶质细胞如何调节大脑回路 并揭示了 Sox9 在控制衰老过程中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，我们提出以下建议 具体目标。在具体目标 1 中，我们将定义解剖学、形态学和生理学 衰老大脑中 CD51+ 和 CD51- 星形胶质细胞的特性以及它们如何发挥作用 海马体和嗅球的电路功能。在具体目标 2 中，我们将使用我们的 星形胶质细胞特异性 Sox9 敲除小鼠破译其如何调节星形胶质细胞功能 大脑老化以及星形胶质细胞的这些变化如何影响海马体和脑部的回路功能 嗅球。在具体目标 3 中，我们将确定 Sox9 在 老化并将我们的发现与 Sox9 ChIP-Seq 相结合，以破译 Sox9 靶基因网络。