Investigating the role of astrocyte specific NFIA during initiation and progression of AD pathogenesis

项目摘要/摘要 星形胶质细胞是成人大脑中含量最丰富、种类最多的胶质细胞，占神经胶质细胞的70%。 选民。星形胶质细胞执行正常大脑功能的基本任务，并对各种神经功能做出贡献 疾病，包括神经退行性疾病，如阿尔茨海默病(AD)。然而，它们在健康中的作用 而疾病仍然是一个谜。最近，我们发现NFIA在星形胶质细胞介导的 大脑回路和大脑中的记忆，它在AD小鼠大脑中的反应性星形胶质细胞中高度增加。 尽管反应性星形胶质细胞与大脑多个区域的变性神经元密切相关 在AD患者中，星形胶质细胞如何在AD的发生和发展中起作用在很大程度上是未知的 星形胶质细胞NFIA如何调节星形胶质细胞和反应性星形胶质细胞的功能。 在这里，使用一个新产生的动物模型，在初步数据中，我们发现-NFIA的得失 在星形胶质细胞中，AD小鼠脑内A积聚减少/增加。这些结果将我们引向 星形胶质细胞NFIA参与星形胶质细胞和反应性星形胶质细胞参与AD发病机制的假说。为了测试 为此，我们提出了一些实验，以证实NFIA在人类AD脑中的表达，并分析AD 不同时间NFIA处理星形胶质细胞后行为学改变在AD小鼠脑内的发病机制 (目标1)。我们接下来询问NFIA如何在AD发病机制中促进星形胶质细胞功能的改变，因为 NFIA调节星形胶质细胞的核心特性。为了测试这一点，我们提出了一些实验来确认A的改变 星形胶质细胞的产生/清除能力、星形胶质细胞钙激活及星形胶质细胞介导 神经传导时间不同的NFIA手法(目标2)。初步数据显示，NFIA规定 海马区星形胶质细胞中的AD相关基因。因此，我们将使用RNA-SEQ和CHIP-SEQ来调查 NFIA在星形胶质细胞和反应性星形胶质细胞中调节AD发病的候选和网络。 此外，我们将在星形胶质细胞和反应性细胞中使用基因操作方法来验证候选 星形胶质细胞从阿尔茨海默病发病的起始阶段到进展阶段(目标3)。 这些结果将揭示星形细胞NFIA是否以及如何在AD发病机制中起作用 星形胶质细胞在阿尔茨海默病的发病过程中起重要作用。为了我的职业发展，这些 研究将在我的导师Deneen博士(星形细胞生物学专家)的指导下提供胶质细胞与AD关系的培训。 同时也是贝勒医学院的扬科夫斯基博士(阿尔茨海默病专家)的共同导师。因为星形胶质细胞 与神经元密切相关，并在所有神经疾病中调节失调，这项提议旨在 揭示星形胶质细胞如何促进神经退行性疾病的发展。为了实现这一目标，拟议的 研究将应用星形胶质细胞生物学的新方法来描述相关的遗传和功能机制 在神经退化的进程中。

Project Summary / Abstract Astrocytes are the most abundant and diverse glial cells in the adult brain, comprising 70% of the glial constituency. Astrocytes perform essential tasks for normal brain function and contribute to various neurological disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). However, their role in health and disease remains a mystery. Recently, we found that NFIA contributes to astrocyte-mediated regulation of brain circuits and memory in the brain, and it was highly increased in reactive astrocytes in the AD mouse brain. Although the reactive astrocytes are closely associated with degenerating neurons across multiple brain regions in patients with AD, it is largely unknown how astrocytes contribute to the initiation and progression of AD and how astrocytic NFIA regulates functions of astrocytes and reactive astrocytes. Here, using a newly generated animal model, in preliminary data, we found that gain or- / loss of- NFIA in astrocytes showed decreasing/increasing of A accumulation in AD mouse brain. These results lead us to the hypothesis that astrocytic NFIA has a role in astrocytes and reactive astrocytes for AD pathogenesis. To test this, we proposed experiments to confirm NFIA expression in the human AD brain and to analyze AD pathogenesis in AD mouse brain with behavioral alteration by time different NFIA manipulation in astrocytes (Aim 1). We next asked how NFIA contributes to the alteration of astrocyte function for AD pathogenesis since NFIA regulates astrocyte core properties. To test this, we proposed experiments to confirm alteration of A production / clearance ability of astrocytes, astrocytes calcium activation and astrocyte mediated neurotransmission by time different NFIA manipulation (Aim 2). Preliminary data revealed that NFIA regulated AD-related genes in hippocampal astrocytes. Therefore, we will use RNA-seq and ChIP-seq to investigate the NFIA-regulated candidates and networks for AD pathogenesis in astrocytes and reactive astrocytes. Furthermore, we will validate the candidates using gene manipulating methods in astrocytes and reactive astrocytes from the initiation to progression stages of AD pathogenesis (Aim 3). These results will reveal whether and how astrocytic NFIA contributes to AD pathogenesis and how astrocytes contribute to AD pathogenesis from initiation to progression. For my career development, these studies will provide training in the glia-AD relationship under my mentor Dr. Deneen (expert in astrocyte biology) and co-mentor Dr. Jankowsky (expert in Alzheimer's disease) at Baylor College of Medicine. Since astrocytes are intimately connected with neurons and are dysregulated in all neurological disorders, this proposal aims to uncover how astrocytes contribute to neurodegenerative disease development. Towards this goal, the proposed research will apply new approaches to astrocyte biology to delineate genetic and functional mechanisms involved in the progression of neurodegeneration.