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.

项目概要 由于缺乏有效的疗法来减缓或预防进展，导致阿尔茨海默病 (AD) 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。 在 AD 大脑中观察到储存细胞内脂质的脂滴积累。 信号分子，是生物膜的重要组成部分，尤其是胆固醇水平。 突触前和突触后区室影响突触传递，从而影响胆固醇的变化。 代谢可能直接诱发神经元功能障碍和其他 AD 相关病理。 虽然大多数研究都集中在神经元上，但非神经元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、血液相互作用的神经胶质细胞。 血管和其他神经胶质细胞，在突触连接和功能的调节中发挥重要作用 最近的研究表明，星形胶质细胞的变化是 AD 病理的潜在驱动因素。 星形胶质细胞在疾病状态下生理功能下降并释放炎症因子。 大脑中胆固醇的主要产生者，AD 中的胆固醇失调也可能主要由 然而，目前还不清楚胆固醇代谢的程度。 AD 星形胶质细胞失调以及可以针对哪些特定基因来逆转这些变化。 我的论文和博士后研究的总体目标是表征胆固醇代谢 目标 1 中的星形胶质细胞的初步数据证明了我使用人类干细胞的能力。 使用多组学和多组学模型研究 AD 患者星形胶质细胞内在变化的模型 在目标 1 中，我建议仔细研究 AD 中胆固醇的失调情况。 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 在 K00 阶段，我建议扩大神经毒性和支持神经元的能力。 这些对体内模型的分析旨在探讨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，这将推动我的长期发展 成为一名独立的神经科学研究人员和首席研究员的长期职业目标 拟议的研究为发展技术专业知识提供了充足的机会。 星形胶质细胞生物学、新陈代谢和分析技术将有助于帮助我建立。 他们还将指导我寻找实验设计、科学交流和资助方面的技能。 符合我的长期研究和职业目标的博士后培训环境。