Interplay between amyloid precursor protein metabolism and ER-mitochondria contact

淀粉样蛋白前体蛋白代谢与内质网线粒体接触之间的相互作用

基本信息

批准号：
10301076
负责人：
Bingwei Lu
金额：
$ 23.61万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301076
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid beta-Protein Amyloid beta-Protein Precursor Amyotrophic Lateral Sclerosis Apoptosis Autophagocytosis Behavioral Biochemical Bioenergetics Biology Brain Brain Diseases Buffers C-terminal Cells Cellular Structures Citric Acid Cycle Clinical Trials Complex DNA Sequence Alteration Defect Degenerative Disorder Dementia Development Differentiation and Growth Disease Drosophila genus Elderly Electron Transport Enzymes Etiology Exhibits Failure Foundations Functional disorder Future Genetic Genetic study Goals Health Homeostasis Human Human Genetics Image Impairment Lead Link Mammalian Cell Mediating Metabolism Mitochondria Modeling Morphogenesis Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organelles Output Parkinson Disease Pathogenesis Pathogenicity Pathologic Patients Pharmacologic Substance Pharmacology Physiological Physiology Positioning Attribute Process Production Proteins Public Health Regulation Research Role Senile Plaques Signal Transduction Site Structure Synapses Synaptic plasticity Testing Whole Organism amyloid formation disease phenotype effective therapy extracellular familial Alzheimer disease fly human old age (65+)in vivo mitochondrial dysfunction novel novel therapeutic intervention presenilin protein function protein metabolism trafficking transmission process uptake

项目摘要

Alzheimer's disease (AD) remains a looming public health crisis, despite intensive research and pharmaceutical development efforts. No effective treatment option is currently available that can halt the disease process. The recent failures of high-profile clinical trials targeting the amyloid plaques and neurofibrillary tangles, the pathological hallmarks of the AD identified by Dr. Alois Alzheimer more than a century ago and the focus of extensive research and pharmaceutical development efforts, suggest that new directions in delineating the pathogenic mechanisms of AD are warranted before effective treatment of the disease can be achieved. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are intimately linked. In addition to the central role of mitochondria in bioenergetics, they are also critically important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+ transients arising from neuronal activation, protecting against the detrimental effects of bursts of Ca2+ influx. Under basal conditions, Ca2+ entry into mitochondria is needed for normal neuronal physiology. The ER- mitochondria contact site (ERMCS) are recognized as key cellular structures regulating mito-Ca2+ homeostasis. Moreover, there is an emerging recognition of ERMCS impairment in neurodegenerative diseases including AD. How ERMCS and mito-Ca2+ homeostasis are altered, and their contribution to disease phenotypes in in vivo settings, however, are not well understood. The goal of this proposal is to test the central hypothesis that an interplay between APP metabolism and ERMCS directs ER-mitochondrial Ca2+ signaling, and that defects in this process contributes to the etiology of AD. To test this hypothesis, we propose to achieve the following Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in a Drosophila AD model and AD patient derived cells; Aim 2. Test the roles of ERMCS proteins that direct mito-Ca2+ homeostasis in mediating APP function in disease pathogenesis. By providing evidence for the involvement of ERMCS and mito-Ca2+ in APP function at the organellar, synaptic, and organismal levels, these studies will lay the foundation for future studies addressing the regulation and function of ERMCS in normal brain physiology, which will significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling in AD and ultimately offer novel therapeutic strategies.

尽管进行了大量研究和研究，阿尔茨海默病（AD）仍然是迫在眉睫的公共卫生危机药物开发努力。目前尚无有效的治疗方案可以阻止这种情况疾病过程。最近针对淀粉样蛋白斑块的备受瞩目的临床试验失败了神经原纤维缠结是阿洛伊斯·阿兹海默 (Alois Albert) 博士发现的 AD 的病理特征。一个世纪前的广泛研究和药物开发工作的重点表明，新的在有效治疗 AD 之前，需要先明确 AD 的致病机制。疾病可以达到。线粒体是动态且复杂的细胞器，在生物学的许多方面发挥着重要作用，从能量产生和中间代谢到细胞内信号传导和细胞凋亡。这些广泛的功能将线粒体定位为人类健康的核心角色。在神经元中，线粒体和突触是密切相关。除了线粒体在生物能学中的核心作用外，它们还至关重要对于维持细胞 Ca2+ 稳态很重要。线粒体摄取 Ca2+ 有助于缓冲胞质 Ca2+ 神经元激活引起的瞬变，防止 Ca2+ 涌入的有害影响。在基础条件下，Ca2+ 进入线粒体是正常神经元生理学所必需的。急诊室- 线粒体接触位点 (ERMCS) 被认为是调节线粒体 Ca2+ 稳态的关键细胞结构。此外，人们越来越认识到神经退行性疾病中的 EMCS 损伤，包括广告。 EMCS 和线粒体 Ca2+ 稳态如何改变，以及它们对疾病表型的贡献然而，vivo 的设置还不太了解。该提案的目标是检验中心假设： APP 代谢和 EMCS 之间的相互作用指导 ER 线粒体 Ca2+ 信号传导，并且该缺陷这一过程促成了 AD 的病因学。为了检验这个假设，我们建议实现以下目标该探索性项目的具体目标：目标 1. 检查果蝇 AD 中 EMCS 形成的缺陷模型和 AD 患者来源的细胞；目标 2. 测试 EMCS 蛋白在指导线粒体 Ca2+ 稳态中的作用介导 APP 在疾病发病机制中的功能。通过提供 EMCS 参与的证据和 mito-Ca2+ 在细胞器、突触和生物体水平的 APP 功能中的作用，这些研究将奠定为未来研究正常脑生理学中 EMCS 的调节和功能奠定基础，这将显着增进我们对线粒体和 Ca2+ 信号传导基本作用的理解并最终提供新颖的治疗策略。