Relationship between Amyloid beta and Bioenergetics

项目摘要/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显的关系。 APP和Aβ影响线粒体功能，而线粒体功能和生物能量通路影响线粒体功能 应用程序处理。一些研究表明，线粒体呼吸流量的减少会减少Aβ的产生。 相反，增加线粒体呼吸通量的参数会增加Aβ的产生。总目标 这项研究的目的是确定生物能量学如何影响APP的处理路径。我们的初步数据 支持线粒体膜电位和活性氧(ROS)在调节细胞周期中的作用 Aβ的制作。基于这些发现，我们假设线粒体膜电位和 线粒体衍生的ROS影响APP的处理。我们将阐明这些生物能量的参与 应用程序处理路径中的中间体，并确定这些变化如何发生。我们假设 生物能量学通过调节APP的细胞定位和运输来影响APP加工路径 APP、β-和γ-分泌酶。为此，我们建议的研究将探索 线粒体、能量代谢相关现象和Aβ的产生。这些研究可能会潜在地 促进我们对阿尔茨海默病(AD)相关级联反应的理解，同时也提供翻译 以及相关的见解。了解β生产和生物能量学之间的关系将提供 关于大脑老化和阿尔茨海默病之间关系的更多线索，以及新的治疗靶点。 这一K99/R00奖项旨在通过赞扬威尔金斯博士目前的培训来进一步推动她的职业道路 以及开发新领域的专业知识。这些新领域包括重新编程诱导的多能干细胞 细胞(Ipscs)、β-和γ-分泌酶生物学。在堪萨斯大学医学中心，威尔金斯博士将 在神经科工作，阿尔茨海默病中心主任(罗素医生 Swerdlow)是她的主要导师。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 共同导师。该奖项的联合导师包括：Kenneth Peterson博士(KUMC)，他将提供 Crispr/Cas9系统和IPSC重新编程方面的专业知识；Robert Vassar博士(西北大学) 世卫组织将提供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(哈佛大学)将 提供γ分泌酶生物学和操作方面的专业知识。协作者将协助评估应用程序 加工(Bruce Yankner博士，哈佛大学)和生物统计分析(Jon Mankhen博士，KUMC)。威尔金斯医生的 专家指导团队和协作者，强大的培训环境，以及先前的研究经验 对于推进她的职业目标来说是势在必行的。

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.