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.

项目概要/摘要 痴呆症在全世界范围内造成了巨大的疾病负担，约有 5000 万人患有该病。阿尔茨海默氏症 疾病（AD），痴呆症最常见的病因，其特征是淀粉样蛋白的异常积累 大脑中的 beta (Aβ) 和 tau 蛋白。 AD 后，路易体痴呆 (DLB) 常常被列为最常见的痴呆症 痴呆症的两种常见形式，其中 α-突触核蛋白 (α-syn) 神经元包涵体是一种关键病理学 标记。尽管 AD 和 DLB 很常见，但神经病理学研究一致指出， 单一潜在病因，患者出现多种病理（混合病理）的频率很高 导致痴呆综合症。这些病理现象在一起时的病理生理学影响 神经退行性变的发生和进展以及认知能力下降的发展尚待确定 全面了解了。 R21 的基础研究是一项临床转化研究，利用系统生物学和 蛋白质组学技术来表征差异表达基因和蛋白质的特性 仅患有 AD 或 DLB 病理的患者以及患有 AD 和 DLB 混合型痴呆病理的患者 DLB病理学。在这项工作中，我们将澄清是否存在某些大脑更容易发育的机制原因 ADP-LRP (Aβ-α-syn) 与其他以 Aβ 或 α-syn 为主的疾病相比具有混合病理学特征。先前的AD研究 和 DLB 表明内体-溶酶体途径失调。作为这些先前研究中的临床 AD 痴呆 通常包括混合病理学，解开内体-溶酶体的作用一直具有挑战性。 每个个体病理的失调。我们的初步数据使我们假设 Aβ 的存在 大脑中的病理学以及共存的细胞囊泡运输异常使其更有可能 包括 ADP-LRP 在内的混合病理学的发展。我们将通过蛋白质组学和 对三个患者组（AD、DLB 和混合 AD-DLB）的大脑、CSF 和血浆进行转录组学评估 年龄和性别与正常对照相匹配。我们将根据其他数据确认并验证我们的数据 大型国家数据（ADNI，加速药品合作伙伴关系-AD）。我们将开发一个模型范式来评估 囊泡转运蛋白失调在遗传、转录和混合病理学中的作用 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 这些病理学之间协同关系的本质，以开发更好的混合治疗靶向 病理性痴呆。如果发现假设不成立，本研究的结果仍将代表 我们对个体蛋白质组学和转录组学特征变异性的了解取得了重大进展 面对神经退行性疾病的病理学。该结果将在临床和设计中都有用 并解释未来的研究成果。