Dysregulated cholesterol metabolism in Alzheimer's Disease astrocytes: Investigating contributions to neuronal dysfunction

项目摘要 由于缺乏有效的治疗方法来减缓或预防进展，阿尔茨海默病（AD） 全球健康危机。炎症、神经元功能障碍和最终的神经元损失是AD的标志。 胆固醇代谢也与AD和其他神经退行性疾病有关。比如说， 在AD脑中观察到储存细胞内脂质的脂滴的积累。胆固醇作为一种 信号分子，是生物膜的重要组成部分。值得注意的是， 突触前和突触后隔室影响突触传递。胆固醇的变化 代谢可直接诱导神经元功能障碍和其他AD相关病理。 虽然大多数研究集中在神经元上，但非神经元胶质细胞在调节神经元细胞的功能中是必不可少的。 功能和维持大脑稳态。星形胶质细胞是一类神经胶质细胞， 血管和其他神经胶质细胞，在调节突触连接和功能中发挥重要作用 在生活中。最近的研究表明，星形胶质细胞的变化是AD病理学的潜在驱动因素。 星形胶质细胞在疾病状态下具有降低的生理功能并释放炎性因子。为 作为大脑中胆固醇的主要生产者，AD中的胆固醇失调也可能主要由以下因素驱动： 星形胶质细胞代谢的变化。但是，胆固醇代谢到什么程度，目前还不清楚 AD星形胶质细胞中的失调以及哪些特定基因可以靶向逆转这些变化。 我的论文和博士后研究的总体目标是描述胆固醇代谢的特征 在AD的背景下，星形胶质细胞中。目标1中的初步数据证明了我使用人类干细胞的能力 使用多组学模型研究来自AD个体的星形胶质细胞的内在变化， 代谢组学方法。在目标1中，我建议仔细研究AD中胆固醇是如何失调的 星形胶质细胞以及这些失调如何促进AD相关的星形胶质细胞功能障碍，例如采用 神经毒性和丧失支持神经元的能力。在K 00阶段，我建议扩大 这些分析用于体内模型以探测星形胶质细胞胆固醇代谢的全系统贡献。 培训计划整合了科学和专业发展活动，将促进我的长期- 长期职业目标成为一个独立的神经科学研究员和首席研究员的一个 学术实验室拟议的研究为发展以下方面的技术专长提供了充分的机会： 星形胶质细胞生物学、代谢和分析技术。我的赞助商将帮助我建立 实验设计、科学交流和语言表达能力。他们也会引导我找到一个 博士后培训环境，符合我的长期研究和职业目标。

Project Summary The absence of effective therapies to slow or prevent progression have made Alzheimer’s Disease (AD) a global health crisis. Inflammation, neuronal dysfunction, and eventual neuronal loss are hallmarks of AD. Cholesterol metabolism is also implicated in AD and other neurodegenerative diseases. For example, accumulation of lipid droplets that store intracellular lipids are observed in AD brains. Cholesterol acts as a signaling molecules and is an essential component of biological membranes. Notably, cholesterol levels in the presynaptic and postsynaptic compartments influence synaptic transmission. Thus, changes to cholesterol metabolism could directly induce neuronal dysfunction and other AD-associated pathology. While most research focuses on neurons, non-neuronal glial cells are essential in regulating neuronal function and maintaining brain homeostasis. Astrocytes are a class of glial cell that interact with synapses, blood vessels, and other glial cells, playing essential roles in the regulation of synaptic connectivity and function throughout life. Recent studies suggest that changes to astrocytes are potential drivers of AD pathology. Astrocytes have decreased physiological functions and release inflammatory factors in disease states. As the main producers of cholesterol in the brain, cholesterol dysregulations in AD could also be primarily driven by changes in astrocyte metabolism. However, it is still unclear to what extent cholesterol metabolism is dysregulated in AD astrocytes and what specific genes could be targeted to reverse these changes. The overall goal of my dissertation and post-doctoral research is to characterize cholesterol metabolism in astrocytes in the context of AD. Preliminary data in Aim 1 demonstrates my ability to use human stem cell models to study intrinsic changes in astrocytes derived from individuals with AD using multi-omic and metabolomic approaches. In Aim 1, I propose taking a closer look at how cholesterol is dysregulated in AD astrocytes and how these dysregulations promote AD-related astrocyte dysfunctions, such as adoption of neurotoxic properties and loss of the ability to support neurons. During the K00 Phase, I propose expanding these analyses to in vivo models to probe system-wide contributions of astrocyte cholesterol metabolism. The Training Plan integrates scientific and professional development activities that will advance my long- term career goals of becoming an independent neuroscience researcher and principal investigator of an academic laboratory. The proposed research provides ample opportunities for developing technical expertise in astrocyte biology, metabolism, and analytical techniques. My Sponsors will be instrumental in helping me build skills in experimental design, scientific communication, and grantsmanship. They will also guide me in finding a postdoctoral training environment that aligns with my long-term research and career goals.