Integrative analysis of proteomics and transcriptomics to delineate vesicular transport related protein abnormalities related to Alzheimer's, Lewy body and mixed Pathologies

蛋白质组学和转录组学的综合分析，以描述与阿尔茨海默病、路易体和混合病理学相关的囊泡运输相关蛋白质异常

• 批准号: 10444050
• 负责人: Gurkan Bebek
• 金额: $ 45.56万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444050
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Data; Dementia; Dementia with Lewy Bodies; Development; Disease; Drug Targeting; Etiology; Evaluation; Foundations; Frequencies; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Transcription; Goals; Impaired cognition; Individual; Injections; Intervention; Knowledge; Lewy Bodies; Lewy body pathology; Liquid Chromatography; Medial; Medicine; Modeling; Molecular; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcomes Research; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Persons; Plasma; Play; Property; Proteins; Proteomics; Public Health; Reaction; Regulation; Reporting; Research; Role; Sampling; Senile Plaques; Symptoms; Syndrome; System; Systems Biology; Techniques; Temporal Lobe; Therapeutic; Time; Transgenic Mice; Vesicular Transport Proteins; Work; abeta accumulation; aging brain; alpha synuclein; base; brain tissue; burden of illness; candidate marker; cognitive development; design; differential expression; gene regulatory network; insight; mixed dementia; mouse model; neuropathology; normal aging; precision medicine; role model; sex; tandem mass spectrometry; tau Proteins; therapeutic target; transcriptome sequencing; transcriptomics; translational study; vesicle transport

PROJECT SUMMARY/ABSTRACT Dementia has a significant disease burden worldwide with around 50 million people having it. Alzheimer’s disease (AD), the most common etiology of dementia is characterized by abnormal accumulation of amyloid beta(Aβ) and tau proteins in the brain. After AD, dementia with Lewy bodies (DLB) is often noted among the top two common forms of dementia and includes α-synuclein protein (α-syn) neuronal inclusions as a key pathology marker. Even as AD and DLB are common, neuropathology studies have consistently noted that rather than a single underlying etiology, there is a high frequency of patients where more than one pathology (mixed pathology) contributes to the dementia syndrome. The pathophysiological impact of these pathologies when together, on the initiation and progression of neurodegeneration and development of cognitive decline is yet to be comprehensively understood. The research at the foundation of this R21 is a clinical translational study that uses systems biology and proteomics techniques to characterize the properties of differentially expressed genes and proteins between patients with AD or DLB pathology alone and among those patients with mixed dementia pathology of AD and DLB pathology. In this work we will clarify if there is a mechanistic reason some brains are more prone to develop mixed pathology of ADP-LRP (Aβ-α-syn) over others that have predominantly Aβ or α-syn. Prior studies in AD and DLB suggest dysregulation of endosomal-lysosomal pathways. As clinical AD dementia in these prior studies often included mixed pathology, it has been challenging to disentangle the role for endosomal-lysosomal dysregulation for each individual pathology. Our preliminary data leads us hypothesize that presence of Aβ pathology in the brain along with co-existing cellular vesicular transport abnormalities makes it more likely for the development of mixed pathologies including ADP-LRP. We will evaluate this hypothesis by proteomic and transcriptomic evaluation of brain, CSF and plasma of three patient groups (AD, DLB and mixed AD-DLB) and among age and sex matched normal controls. We will confirm and validate our data against data from other large national data (ADNI, Accelerating Medicines Partnership-AD). We will develop a model paradigm to assess the role for dysregulation of vesicular transport proteins in mixed pathologies at the genetic, transcriptional and proteomic levels. If the hypothesis and models are validated, scientific insights from this research will help identify the nature of synergistic relationship between these pathologies to develop better therapeutic targeting of mixed pathology dementia. If the hypothesis is found to be not true, the findings from this study will still represent a significant advance in our knowledge of variability in individual proteomic and transcriptomic signatures in the face of neurodegenerative disease pathology. The results of this will be useful both clinically and in designing and interpreting future research outcomes.

项目摘要/摘要 痴呆症在全球范围内造成了严重的疾病负担，约有5000万人患有痴呆症。阿尔茨海默氏症 阿尔茨海默病(AD)是痴呆最常见的病因，其特征是淀粉样蛋白的异常堆积 大脑中的β(Aβ)和tau蛋白。在阿尔茨海默病之后，路易体痴呆(DLB)通常是最常见的 痴呆的两种常见形式，包括α-突触核蛋白(α-SYN)神经元包涵体是一种关键病理 记号笔。尽管AD和DLB很常见，但神经病理学研究一直指出，与其 单一的潜在病因，有高频率的患者其中有一种以上的病理(混合病理) 会导致痴呆症。当这些病理因素结合在一起时，对 神经退行性变和认知功能减退的发生和发展尚不清楚。 全面了解。 R21的基础研究是一项临床转化研究，使用了系统生物学和 用蛋白质组学技术研究差异表达基因和蛋白质的特性 仅有AD或DLB病理的患者以及AD和DLB的混合性痴呆患者 DLB病理学。在这项工作中，我们将阐明是否存在一些大脑更容易发育的机械性原因 ADP-LRP(Aβ-α-SYN)的混合病理高于其他以Aβ或α-SYN为主的疾病。AD的前期研究 和DLB提示内切酶-溶酶体途径调节失调。在这些先前的研究中作为临床阿尔茨海默病 通常包括混合病理，要弄清内体-溶酶体的作用是具有挑战性的。 每一种病理的失调。我们的初步数据让我们假设β的存在 大脑中的病理以及共存的细胞泡泡运输异常使其更有可能 包括ADP-LRP在内的混合病理的发展。我们将通过蛋白质组学和蛋白质组学来评估这一假设 三组患者(AD、DLB和混合型AD-DLB)脑、脑脊液和血浆的转录水平评价 在年龄和性别匹配的正常对照组中。我们将根据来自其他公司的数据确认和验证我们的数据 大型国家数据(ADNI，加速药物伙伴关系-AD)。我们将开发一个模型范例来评估 囊泡转运蛋白在基因、转录和转录水平的混合病理中的作用 蛋白质组水平。如果假设和模型得到验证，这项研究的科学见解将有助于确定 这些病理之间的协同关系的性质，以开发更好的混合靶向治疗 病理性痴呆。如果这一假设被发现是不正确的，这项研究的结果仍然代表着 我们对个体蛋白质组和转录组特征的可变性的了解取得了重大进展 面对神经退行性疾病的病理。这一结果在临床和设计中都是有用的。 并解读未来的研究成果。