Relationship between Amyloid beta and Bioenergetics

β淀粉样蛋白与生物能学的关系

• 批准号: 10084215
• 负责人: Heather M. Wilkins
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084215
• 关键词: Abeta synthesis; Acids; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Award; Biochemistry; Bioenergetics; Biology; Biometry; C-terminal; CRISPR/Cas technology; Career Choice; Cell Survival; Cell membrane; Data; Deoxyglucose; Development; Elderly; Electron Transport; Endosomes; Energy Metabolism; Environment; Enzymes; Event; Fibroblasts; Gap Junctions; Generations; Glucose; Glycolysis Inhibition; Goals; Grant; Human; Impairment; Individual; Induced pluripotent stem cell derived neurons; Intervention; Kansas; Length; Measures; Mediating; Medical center; Membrane Microdomains; Membrane Potentials; Mentors; Mitochondria; Modeling; Mutate; Neurology; Neurons; Oligomycins; Pathway interactions; Phosphorylation; Post-Translational Protein Processing; Production; Reactive Oxygen Species; Research; Role; SOD2 gene; System; Techniques; Testing; Training; Universities; Work; aging brain; amyloid precursor protein processing; base; beta secretase; beta-site APP cleaving enzyme 1; career; catalase; cholinergic; deprivation; design; experience; gamma secretase; glycosylation; induced pluripotent stem cell; insight; knock-down; mitochondrial membrane; new therapeutic target; novel; overexpression; palmitoylation; presenilin; presenilin-1; presenilin-2; respiratory; secretase; skills; trafficking; trans-Golgi Network

Project Summary/Abstract A clear relationship between amyloid precursor protein (APP), amyloid beta (Aβ), and mitochondria exists. APP and Aβ influence mitochondrial function, while mitochondrial function and bioenergetic pathways influence APP processing. Several studies indicate reductions in mitochondrial respiratory flux decrease Aβ production. Conversely, parameters which increase mitochondrial respiratory flux increase Aβ production. The overall goal of this study is to determine how bioenergetics influence APP processing pathways. Our preliminary data support a role for mitochondrial membrane potential and reactive oxygen species (ROS) in modulating the production of Aβ. Based on these findings, we hypothesize mitochondrial membrane potential and mitochondrial derived ROS influence APP processing. We will elucidate the involvement of these bioenergetic intermediates in APP processing pathways and determine how these changes occur. We hypothesize bioenergetics influence APP processing pathways by modulating the cellular localization and trafficking of APP, β-, and γ-secretases. To this end our proposed studies will explore fundamental relationships between mitochondria, energy metabolism-related phenomena, and Aβ production. These studies could potentially advance our understanding of Alzheimer’s disease (AD)-associated cascades while also providing translational and relevant insight. Understanding the relationship between Aβ production and bioenergetics will provide additional clues to the nexus between brain aging and AD, and novel therapeutic targets. This K99/R00 award is designed to further Dr. Wilkins’ career path by complimenting her current training and developing expertise in new areas. These new areas include reprogramming induced pluripotent stem cells (iPSCs), β-, and γ-secretase biology. At the University of Kansas Medical Center (KUMC), Dr. Wilkins will work in the neurology department, where the director of the Alzheimer’s Disease Center (Dr. Russell Swerdlow) is her primary mentor. To facilitate training in new techniques Dr. Wilkins will be assisted by a group of co-mentors. The co-mentors for this award include: Dr. Kenneth Peterson (KUMC) who will provide expertise on Crispr/Cas9 systems and reprogramming iPSCs; Dr. Robert Vassar (Northwestern University) who will provide expertise on β-secretase biology and manipulations, and Dr. Michael Wolfe (Harvard) who will provide expertise on γ-secretase biology and manipulations. Collaborators will assist with measuring APP processing (Dr. Bruce Yankner, Harvard) and biostatistical analysis (Dr. Jon Mankhen, KUMC). Dr. Wilkins’ expert mentoring team and collaborators, strong training environment, and prior research experience are imperative for advancing her career goals.

项目总结/摘要 淀粉样前体蛋白（APP）、淀粉样β蛋白（Aβ）和线粒体之间存在明确的关系。 APP和Aβ影响线粒体功能，而线粒体功能和生物能量途径影响 APP处理。几项研究表明，线粒体呼吸通量的减少会降低Aβ的产生。 相反，增加线粒体呼吸通量的参数增加Aβ的产生。总目标 本研究的目的是确定生物能量学如何影响APP加工途径。我们的初步数据 支持线粒体膜电位和活性氧（ROS）在调节线粒体膜电位中的作用。 Aβ的产生。基于这些发现，我们假设线粒体膜电位， 线粒体源性ROS影响APP加工。我们将阐明这些生物能 APP加工途径中的中间体，并确定这些变化如何发生。我们假设 生物能量学通过调节细胞定位和运输 APP、β-和γ-分泌酶。为此，我们提出的研究将探讨基本关系， 线粒体、能量代谢相关现象和Aβ产生。这些研究有可能 推进我们对阿尔茨海默病（AD）相关级联的理解，同时也提供翻译 相关的洞察力。了解Aβ产生与生物能量学之间的关系将为我们提供 大脑老化和AD之间的联系的额外线索，以及新的治疗靶点。 这个K99/R 00奖项旨在通过赞扬她目前的培训来进一步发展Wilkins博士的职业道路 并在新领域发展专业知识。这些新领域包括重编程诱导多能干细胞 细胞（iPSC）、β-和γ-分泌酶生物学。在堪萨斯大学医学中心（KUMC），威尔金斯博士将 我在神经科工作，那里的阿尔茨海默病中心主任（罗素博士 ”（《明史》）是他的主要导师。为了促进新技术的培训，威尔金斯博士将得到一个小组的协助。 的共同导师。该奖项的共同导师包括：Kenneth Peterson博士（KUMC），他将提供 Crispr/Cas9系统和iPSCs重编程的专业知识; Robert Vassar博士（西北大学） 他将提供β-分泌酶生物学和操作方面的专业知识，迈克尔沃尔夫博士（哈佛）将 提供γ-分泌酶生物学和操作方面的专业知识。合作者将协助测量APP 处理（布鲁斯扬克纳博士，哈佛）和生物统计学分析（乔恩曼肯博士，KUMC）。威尔金斯医生 专家指导团队和合作者，强大的培训环境，以及先前的研究经验， 这对她的职业目标至关重要。