Novel misfolded proteins in ADRD: proteomics, genetics, and clinical-pathological correlations

ADRD 中的新型错误折叠蛋白：蛋白质组学、遗传学和临床病理相关性

• 批准号: 9905466
• 负责人: PETER T. NELSON
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905466
• 关键词: Age; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Animal Model; Automobile Driving; Autopsy; Biochemical; Biochemistry; Biological Markers; Brain; Brain Diseases; Candidate Disease Gene; Cessation of life; Chromosome Mapping; Clinical; Clinical Data; Core Facility; Correlation Studies; Data; Databases; Dementia; Detergents; Development; Diagnostic; Disease; Education; Elderly; Electrospray Ionization; Freezing; Funding Mechanisms; Future; Genes; Genetic; Genetic study; Genie; Genomics; Goals; Hand; Heterogeneity; Human; Image; Immunohistochemistry; Impaired cognition; Impairment; Individual; Kentucky; Knowledge; Liquid Chromatography; Mass Spectrum Analysis; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenicity; Pathologic; Pathology; Persons; Process; Proteins; Proteome; Proteomics; Public Health; Reporting; Research; Research Project Grants; Sampling; Seasons; Series; Severities; Statistical Data Interpretation; Statistical Models; TDP-43 aggregation; Testing; Therapeutic; Universities; University resources; Urea; Work; aged; aging brain; alpha synuclein; base; biobank; cerebrovascular pathology; clinical Diagnosis; cohort; demented; endophenotype; frontotemporal lobar dementia-amyotrophic lateral sclerosis; genetic risk factor; genetic variant; insight; large scale data; misfolded protein; multidisciplinary; neuropathology; novel; polypeptide; protein TDP-43; protein misfolding; sex; synuclein; tandem mass spectrometry; tau Proteins

The heterogeneous pathologies of Alzheimer's disease and related dementias (ADRD) are still incompletely understood. There is no perfect animal model to study these diseases. Four known aberrantly misfolded proteins are commonly detected via neuropathologic examination of brains with ADRD: Aβ, Tau, TDP-43, and/or α-Synuclein. Our preliminary data indicate that there are more pathogenic protein species awaiting identification. Characterization of these proteins may be relevant to the development of both diagnostic and therapeutic strategies for ADRD. The goals of this research project are to identify previously uncharacterized, misfolded, and aberrantly processed proteins in ADRD; to resolve gene variants that modulate the severity and heterogeneity of dementia through the novel misfolded proteins; and, to perform clinical-pathological correlation, focusing on these novel proteins, to identify new disease-associated pathologic biomarkers. We will leverage the resources of the University of Kentucky AD Center (UK-ADC) biobank and the University of Kentucky Proteomics Core Facility, to execute the following Specific Aims: Specific Aim 1. Analyse detergent-insoluble protein extracts from human amygdala (snap-frozen at autopsy) to investigate whether as yet uncharacterized misfolded proteins are detectable in ADRD. Polypeptides from the detergent-insoluble, urea-soluble protein fractions of amygdala will be interrogated using mass spectrometry. We have on-hand amygdalae from 40 UK-ADC subjects which incorporate a spectrum of clinical and pathologic features. Immunohistochemistry and biochemical studies will be performed to determine the best candidate proteins for additional studies (Aims 2 and 3). Specific Aim 2. Construct a robust and harmonized database with exonic sequencing to localize genetic regions associated with novel misfolded proteins in ADRD. We will test the association between dementia and rare, exonic (`mis-sense') genetic variants in genes that encode candidate misfolded proteins (Aim 1). Genetics data augmented with rich neuropathologic endophenotypes and longitudinal clinical data will enable insights into novel mechanisms that drive dementia. Large-scale datasets (NACC, ADGC, ADSP) will be aggregated and harmonized to test the genetic drivers of clinical and neuropathology-based endophenotypes focusing on novel candidate genes. Candidate target genes have already been identified. Specific Aim 3. Establish the clinical-pathologic correlation for the novel misfolded proteinopathies in ADRD. We will test the association between the potential novel proteinopathies (from Aim 1) with cognitive impairment, factoring in known markers Aβ, tau, α-Synuclein, and TDP-43, as well as cerebrovascular pathologies. We have 370 samples available for analyses (both sexes) from the UK-ADC, which should be statistically powered to test our hypothesis that the presence and severity of novel misfolding protein pathologies are associated with cognitive impairment.

阿尔茨海默氏病和相关痴呆症（ADRD）的异质性病理仍然是 不完全理解。没有完美的动物模型来研究这些疾病。异常已知四个 通常通过对ADRD：Aβ，TAU， TDP-43和/或α-核蛋白。我们的初步数据表明有更多的致病蛋白 等待识别的物种。这些蛋白质的表征可能与 ADRD的诊断和治疗策略。该研究项目的目标是确定 在ADRD中，以前未表征，错误折叠和异常处理的蛋白质；解决基因变体 通过新型错误折叠的蛋白质调节痴呆症的严重程度和异质性。而且，要 进行临床病理相关性，重点是这些新型蛋白质，以鉴定与疾病相关的新蛋白 病理生物标志物。我们将利用肯塔基大学广告中心（UK-ADC）的资源 生物库和肯塔基大学的蛋白质组学核心设施，以执行以下特定目标： 特定目的1。分析从人杏仁核（snap-frozen）确定不溶性蛋白质提取物 在尸检时）研究是否可以在ADRD中检测到尚未表征的错误折叠蛋白。 杏仁核的确定不溶性，尿素可溶性蛋白级分的多肽将被询问 使用质谱法。我们有来自40个UK-ADC主题的杏仁核 临床和病理特征的光谱。免疫组织化学和生化研究将是 进行其他研究的最佳候选蛋白（目标2和3）。 特定目标2。构建一个具有外显子测序的强大而协调的数据库以本地化 与ADRD中新型错误折叠蛋白有关的遗传区域。我们将测试 痴呆和稀有的外显子（“失误”）遗传变异的基因中，编码候选蛋白质折叠蛋白的基因 （目标1）。具有丰富神经病理学的内表型和纵向临床数据的遗传学数据将增强 大型数据集（NACC，ADGC，ADSP）将 汇总并协调以测试基于临床和神经病理学的遗传驱动因素 注重新颖候选基因的内型型。候选靶基因已经被鉴定出来。 特定目的3。建立新颖错误折叠的临床病理相关性 ADRD中的蛋白质病。我们将测试潜在的新型蛋白质病之间的关联（来自 目标1）具有认知障碍，在已知标记的Aβ，TAU，α-突触核蛋白和TDP-43以及 脑血管病理。我们有370个样本可用于分析（两个性别），英国-ADC， 应该在统计上供电，以检验我们的假设，即新颖的存在和严重性 错误折叠的蛋白质病理与认知障碍有关。