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

阿尔茨海默病星形胶质细胞中胆固醇代谢失调：研究对神经元功能障碍的影响

• 批准号: 10755162
• 负责人: Jillybeth Burgado
• 金额: $ 4.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755162
• 关键词: Address; Adoption; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; American; Apolipoproteins; Astrocytes; Behavioral; Bioinformatics; Biological; Biological Assay; Biology; Blood Vessels; Brain; Cause of Death; Cell Communication; Cells; Cholesterol; Cholesterol Homeostasis; Communication; Cytokine Signaling; Data; Data Set; Databases; Dementia; Development; Diagnosis; Disease; Doctor of Philosophy; Environment; Exhibits; Experimental Designs; Exposure to; Extracellular Matrix; Functional disorder; Generations; Genes; Goals; Health; Homeostasis; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Laboratories; Life; Lipids; Lipoproteins; Measures; Membrane; Metabolic; Metabolic Pathway; Metabolism; Multiomic Data; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Neurosciences; Outcome; Pathology; Pathway interactions; Patients; Phase; Phenotype; Physiological; Play; Postdoctoral Fellow; Principal Investigator; Property; Proteome; Regulation; Research; Research Personnel; Research Project Grants; Role; Signal Transduction; Signaling Molecule; Source; Synapses; Synaptic Transmission; System; Technical Expertise; Techniques; Training; Transgenic Mice; Transgenic Model; United States; Viral; Wild Type Mouse; age related neurodegeneration; candidate identification; career; cell type; comparison control; effective therapy; experimental study; global health; human stem cells; in vivo; in vivo Model; induced pluripotent stem cell; knock-down; lipid metabolism; lipid transport; metabolomics; mouse model; multi-electrode arrays; multiple omics; neuron loss; neurotoxic; novel; overexpression; post-doctoral training; postsynaptic; presynaptic; prevent; response; skills; stable isotope; stem cell model; synaptogenesis; trafficking; transcriptome; uptake

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.

项目摘要 缺乏有效的疗法来减慢或预防进展，使阿尔茨海默氏病（AD） 全球健康危机。炎症，神经元功能障碍和最终神经元丧失是AD的标志。 AD和其他神经退行性疾病也实施了胆固醇代谢。例如， 在AD大脑中观察到储存细胞内脂质的脂质液滴的积累。胆固醇充当 信号分子是生物膜的重要组成部分。值得注意的是，胆固醇水平 突触前和突触后室影响突触传播。那就改变了胆固醇 代谢可以直接诱导神经元功能障碍和其他与AD相关的病理。 虽然大多数研究侧重于神经元，但非神经神经胶质细胞对于调节神经元至关重要 功能和维持大脑稳态。星形胶质细胞是一类与突触相互作用的神经胶质细胞 血管和其他神经胶质细胞在调节突触连通性和功能中起着重要作用 一生。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。 星形胶质细胞改善了生理功能并释放疾病状态的炎症因子。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是由主要驱动的 星形胶质细胞代谢的变化。但是，尚不清楚胆固醇代谢在多大程度上是 在AD星形胶质细胞中的失调以及可以靶向哪些特定基因来扭转这些变化。 我的论文和博士后研究的总体目标是表征胆固醇代谢 在AD背景下的星形胶质细胞中。 AIM 1中的初步数据证明了我使用人类干细胞的能力 研究使用多摩尼克和 代谢组方法。在AIM 1中，我建议仔细研究AD中胆固醇的失调 星形胶质细胞以及这些失调如何促进与广告相关的星形胶质细胞功能障碍，例如采用 神经毒性的特性和支持神经元的能力的丧失。在K00阶段，我建议扩展 这些分析对体内模型进行了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，这将使我长期以来迈进 成为独立神经科学研究人员和主要研究人员的职业生涯目标 学术实验室。拟议的研究为开发技术专长提供了足够的机会 星形胶质细胞生物学，代谢和分析技术。我的赞助商将有助于帮助我建造 实验设计，科学交流和授予技巧的技能。他们还将指导我找到一个 博士后培训环境与我的长期研究和职业目标保持一致。