Interactions between Mitochondria, ER, and Amyloid

线粒体、ER 和淀粉样蛋白之间的相互作用

基本信息

  • 批准号:
    10751909
  • 负责人:
  • 金额:
    $ 3.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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蛋白的存在而诊断的最常见的痴呆形式 大脑内的缠结和淀粉样蛋白β(Aβ)斑块。Aβ由淀粉样前体蛋白(APP)产生, 一种膜蛋白APP和Aβ定位于线粒体及其相关膜 (MAMs)。MAMs是内质网(ER)-线粒体接触位点,并与改变的 ER和线粒体的功能。之前的研究表明,MAM活动直接影响 APP加工成Aβ。我们假设APP在线粒体和MAMs的定位决定了Aβ 生产 先前的研究表明,APP在线粒体、ER和MAMs的定位影响它们的功能,但是, 总体机制尚不清楚。线粒体和ER功能障碍在AD中观察到。受损 线粒体生物能量学,增加氧化应激,改变线粒体钙,胆固醇, 磷脂代谢在AD模型中很明显。已知MAMs调节这些功能性 线粒体和ER之间的模式,并在AD中观察到MAMs的上调。这种上调 假设MAM功能驱动APP加工成Aβ并破坏线粒体和ER功能。 我们将从两个方面来检验我们的假设。我们将阐明APP定位对Aβ 生产和评估MAM功能是否影响APP的定位。我们将讨论APP和Aβ 生产与MAM功能相互作用。我们还将评估AD和细胞类型之间的具体变化, 关系。解决MAMs、APP和Aβ产生之间的关系将提供新的见解 他们在AD病理学中的角色 这个F31奖项旨在通过赞扬她目前的培训来进一步推动Taylor Strope的职业道路 并在新领域发展专业知识。这些新领域包括基因组编辑和诱导分化 多能干细胞(iPSC)、线粒体/ER生物学和APP生物学。在堪萨斯医科大学 中心(KUMC),泰勒Strope将与她的导师,威尔金斯博士和阿尔茨海默氏症的Swerdlow 疾病研究中心。专家指导团队,强大的培训环境和研究经验 对推进泰勒·斯特罗普的学术生涯目标至关重要。

项目成果

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Taylor A. Strope其他文献

Taylor A. Strope的其他文献

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