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

基本信息

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
项目类别：
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&apos 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

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&apos 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

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项目摘要

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.

CWOW研究人员使用梅奥诊所脑库的尸体后脑组织良好，将探测LBD中Aβ和α-Synn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具有行政核心，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的监督，管理和报告功能。神经病理学和生物化学核心将为所有项目提供神经性良好的LBD脑样本和定量内表型。研究项目是由高素质的研究人员领导的，他们专注于LBD的完成和基本方面。项目1将探索LBD的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构建网络分析，这将提供有关潜在疾病机制的见解。项目2将在LBD大脑中识别和验证蛋白质和低多余的生物活性脂质物种，这可能对LBD的独特病理特征很重要。项目3将使用最先进的冷冻EM技术来表征LBD脑中α-Syn和Aβ细丝的天然和分子结构，以产生对这种疾病中蛋白质聚集体的病因学，毒性和蛋白质聚集体的新颖见解。项目4将隔离并表征来自尸体后大脑的Aβ和α-Syn亚种，并使用细胞模型来揭示机械洞察力洞悉导致疾病发病机理的有毒途径。我们设想，在资助期结束时，我们将在理解LBD的独特结构和分子特征以及Aβ和α-Syn之间的遗传和相互作用方面取得重大进展，从而有助于LBD的独特症状，进展以及潜在的病理学。