Interactions between Mitochondria, ER, and Amyloid

线粒体、ER 和淀粉样蛋白之间的相互作用

• 批准号: 10751909
• 负责人: Taylor A. Strope
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-06 至 2028-08-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751909
• 关键词: Abeta synthesis; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Astrocytes; Award; Bioenergetics; Biological Assay; Biology; Brain; CRISPR/Cas technology; Career Choice; Centrifugation; Cholesterol Esters; Cholesterol Homeostasis; Data; Dementia; Diagnosis; Electron Microscopy; Endoplasmic Reticulum; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; Fellowship; Functional disorder; Generations; Goals; Grant; Human; Impairment; In Situ; Induced pluripotent stem cell derived neurons; Integral Membrane Protein; Kansas; Ligation; Medical center; Membrane; Mentors; Methods; Mitochondria; Modality; Mutation; Neurofibrillary Tangles; Neurons; Oxidative Stress; Pathologic; Phospholipid Metabolism; Phospholipids; Postdoctoral Fellow; Production; Research; Role; Sampling; Site; Testing; Training; Universities; Up-Regulation; Western Blotting; Work; amyloid precursor protein processing; beta secretase; calcium metabolism; career; cell type; design; experience; genome editing; induced pluripotent stem cell; insight; membrane activity; membrane assembly; mitochondrial metabolism; new therapeutic target; non-demented; novel; stem cell model; tau Proteins

Project Summary and Abstract Alzheimer’s disease (AD) is the most common form of dementia diagnosed through the presence of tau tangles and amyloid beta (Aβ) plaques within the brain. Aβ is generated from amyloid precursor protein (APP), an integral membrane protein. APP and Aβ localize to mitochondria and mitochondrial associated membranes (MAMs). MAMs are endoplasmic reticulum (ER)-mitochondria contact sites and are associated with altered function of both the ER and mitochondria. Previous studies have shown that MAM activity directly influences APP processing into Aβ. We hypothesize that localization of APP at mitochondria and MAMs dictates Aβ production. Prior studies indicate APP localization at the mitochondria, ER, and MAMs affects their function, but an overall mechanism is not understood. Mitochondrial and ER dysfunction are observed in AD. Impaired mitochondrial bioenergetics, increased oxidative stress, and altered mitochondrial calcium, cholesterol, and phospholipid metabolism are evident in models of AD. MAMs are known to modulate these functional modalities between mitochondria and ER, and upregulation of MAMs is observed in AD. This upregulation of MAM function is hypothesized to drive APP processing into Aβ and disrupt mitochondrial and ER function. We will test our hypothesis in two aims. We will elucidate the effects of APP localization on Aβ production and evaluate if MAM function influences localization of APP. We will address how APP and Aβ production interact with MAM function. We will also evaluate AD and cell-type specific changes between these relationships. Addressing the relationship between MAMs, APP, and Aβ production will provide novel insights into their roles in AD pathology. This F31 award is designed to further Taylor Strope’s career path by complimenting her current training and developing expertise in new areas. These new areas include genome editing and differentiation of induced pluripotent stem cells (iPSCs), mitochondrial/ER biology, and APP biology. At the University of Kansas Medical Center (KUMC), Taylor Strope will work with her mentors, Drs. Wilkins and Swerdlow of the Alzheimer’s Disease Research Center. The expert mentoring team, strong training environment, and research experience are imperative for advancing Taylor Strope’s academic career goals.

项目概要和摘要 阿尔茨海默病 (AD) 是通过 tau 蛋白诊断的最常见痴呆症 大脑内的缠结和β淀粉样蛋白(Aβ)斑块 Aβ是由淀粉样蛋白前体蛋白(APP)产生的， APP 和 Aβ 定位于线粒体和线粒体相关膜。 （MAM）是内质网（ER）-线粒体接触位点，与改变有关。 先前的研究表明，MAM 活性直接影响 ER 和线粒体的功能。 我们勇敢地面对 APP 在线粒体和 MAM 中的定位决定了 Aβ。 生产。 先前的研究表明 APP 在线粒体、ER 和 MAM 上的定位会影响它们的功能，但 AD 中观察到线粒体和 ER 功能障碍的总体机制尚不清楚。 线粒体生物能量学、氧化应激增加以及线粒体钙、胆固醇和 众所周知，AD 模型中的磷脂代谢可以调节这些功能。 线粒体和 ER 之间的模式，并且在 AD 中观察到 MAM 的上调。 MAM 功能被重新捕获，驱动 APP 加工成 Aβ，并破坏线粒体和 ER 功能。 我们将在两个目标上检验我们的假设。我们将阐明 APP 本地化对 Aβ 的影响。 生产并评估 MAM 功能是否影响 APP 的本地化 我们将讨论 APP 和 Aβ 如何进行。 我们还将评估 AD 和细胞类型之间的特定变化。 解决 MAM、APP 和 Aβ 生产之间的关系将提供新的见解。 深入了解他们在 AD 病理学中的作用。 F31 奖项旨在通过补充 Taylor Strope 目前的训练来进一步推进她的职业道路 并发展新领域的专业知识，包括基因组编辑和诱导分化。 堪萨斯大学医学院的多能干细胞 (iPSC)、线粒体/ER 生物学和 APP 生物学。 中心 (KUMC)，泰勒·斯特罗普 (Taylor Strope) 将与她的导师、阿尔茨海默氏症患者威尔金斯 (Wilkins) 博士和斯沃德洛 (Swerdlow) 博士一起工作。 疾病研究中心专家导师团队、雄厚的培训环境、研究经验。 对于推进泰勒·斯特罗普的学术职业目标至关重要。