Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia

路易体痴呆中β淀粉样蛋白和α-突触核蛋白的协同相互作用

• 批准号: 10237297
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 289.54万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237297
• 关键词: Address; Alleles; Amyloid beta-Protein; Apolipoprotein E; Arizona; Autopsy; Biochemistry; Biometry; Brain; Cell Nucleus; Cell model; Cells; Characteristics; Clinic; Clinical; Cryoelectron Microscopy; Data; Dementia with Lewy Bodies; Development; Diagnostic; Disease; Disease Progression; Doctor of Philosophy; Etiology; Filament; Funding; Future; Genetic; Goals; Heterogeneity; Institution; Intervention; Lead; Lewy Body Dementia; Lewy body pathology; Lipids; Medical Genetics; Molecular; Molecular Structure; Molecular and Cellular Biology; Neurons; Other Genetics; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Process; Proteins; Proteomics; Reporting; Research; Research Personnel; Research Project Grants; Resources; Saint Jude Children' s Research Hospital; Sampling; Standardization; Structural Biochemistry; Structure; Symptoms; Technical Expertise; Techniques; Toxic effect; Transcript; Work; alpha synuclein; apolipoprotein E-4; brain tissue; clinically relevant; dementia risk; drug discovery; druggable target; endophenotype; genetic risk factor; insight; interdisciplinary approach; lipidomics; multidisciplinary; neuropathology; neurotoxicity; novel; prevent; protein aggregation; structural biology; therapy development; transcriptomics

The overarching goal of this proposed Lewy body dementia (LBD) center without walls (CWOW) is to understand synergistic interactions of amyloid-beta (Aβ) and alpha-synuclein (α-syn) and to determine how genetic risk factors, such as apolipoprotein E4, contribute to LBD pathogenesis. Using well-characterized postmortem brain tissue from the Mayo Clinic Brain Bank, CWOW investigators will probe genetics, transcriptomics, proteomics, lipidomics, structure, biochemistry, and function of Aβ and α-syn species in LBD. The CWOW has an Administrative Core and a Neuropathology and Biochemistry Core, as well as four research projects. The Administrative Core will provide fiscal and scientific oversight, management, and reporting functions. The Neuropathology and Biochemistry Core will provide neuropathologically well- characterized LBD brain samples and quantitative endophenotypes to all projects. The research projects are led by highly qualified investigators who focus on complementary and fundamental aspects of LBD. Project 1 will explore genetic correlates of clinical and pathologic heterogeneity of LBD, as well as cell-specific transcript data from single nuclei sequencing to build network analyses, which will provide insights into underlying disease mechanisms. Project 2 will identify and validate proteins and low-abundant bioactive lipid species in LBD brains that may be important to the unique pathologic signature of LBD. Project 3 will use state-of-the–art cryo-EM techniques to characterize the native and molecular structures of α-syn and Aβ filaments in LBD brain to generate novel insight into the etiology, toxicity and spreading of protein aggregates in this disease. Project 4 will isolate and characterize Aβ and α-syn subspecies from postmortem brains and use cellular models to reveal mechanistic insight into toxic pathways contributing to disease pathogenesis. We envision that, at the conclusion of the funding period, we will have made significant progress towards understanding unique structural and molecular features of LBD and how genetics and interactions between Aβ and α-syn contribute to the unique symptoms, progression, and underlying pathology of LBD.

该无壁路易体痴呆（LBD）中心（CWOW）的总体目标是了解淀粉样蛋白- β (Aβ)和α-突触核蛋白（α-syn）的协同相互作用，并确定遗传风险因素，如载脂蛋白E4，如何参与LBD的发病机制。利用来自梅奥诊所脑库的具有良好特征的死后脑组织，CWOW研究人员将探索LBD中Aβ和α-syn物种的遗传学、转录组学、蛋白质组学、脂质组学、结构、生物化学和功能。CWOW有一个行政核心和一个神经病理学和生物化学核心，以及四个研究项目。行政核心将提供财政和科学监督、管理和报告职能。神经病理学和生物化学核心将为所有项目提供神经病理学上表征良好的LBD脑样本和定量的内表型。研究项目由高素质的研究人员领导，他们专注于LBD的互补和基础方面。项目1将探索LBD临床和病理异质性的遗传相关性，以及来自单核测序的细胞特异性转录物数据，以建立网络分析，这将为潜在的疾病机制提供见解。项目2将鉴定和验证LBD大脑中可能对LBD独特病理特征重要的蛋白质和低丰度生物活性脂质。项目3将使用最先进的冷冻电镜技术来表征LBD大脑中α-syn和a - β细丝的天然和分子结构，以对这种疾病中蛋白质聚集体的病因、毒性和扩散产生新的见解。项目4将从死后的大脑中分离和表征Aβ和α-syn亚种，并使用细胞模型揭示有助于疾病发病的毒性途径的机制。我们预计，在资助期结束时，我们将在理解LBD独特的结构和分子特征以及遗传和Aβ和α-syn之间的相互作用如何促进LBD独特的症状、进展和潜在病理方面取得重大进展。