Utilization of proteomics and lipidomics to identify modifiers of LBD

利用蛋白质组学和脂质组学鉴定 LBD 修饰剂

基本信息

批准号：
10237301
负责人：
JUNMIN PENG
金额：
$ 67.48万
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/10237301
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Amygdaloid structure Amyloid beta-Protein Animal Model Antibodies Binding Biological Assay Brain Cell membrane Cerebellum Characteristics Clinical Complex DNA Data Dementia Dementia with Lewy Bodies Deposition Development Diagnosis Disease Event Functional disorder Genes Genome Genomics Genotype Goals Hippocampus (Brain)Human Immunoblotting Immunohistochemistry Lewy Bodies Lewy Body Dementia Lewy body pathology Link Lipids Mass Spectrum Analysis Membrane Modification Molecular Molecular Profiling Nerve Degeneration Paper Parkinson Disease Pathogenesis Pathology Pathway interactions Phosphorylation Population Post-Translational Protein Processing Precipitation Proteins Proteome Proteomics Psychoses RNA RNA Splicing Reporting Research Research Personnel Resources Role Senile Plaques Severities Signal Transduction Site-Directed Mutagenesis Solubility Specimen Spliceosomes Structure Substantia nigra structure Systems Biology Technology Temporal Lobe Tissue Sample U1 Small Nuclear Ribonucleoprotein Ubiquitination alpha synuclein base brain tissue cell type clinically relevant cohort frontal lobe gene function innovation lipid metabolism lipidome lipidomics mind control molecular marker multidisciplinary novel potential biomarker pre-clinical prevent protein biomarkers transcriptome

项目摘要

Summary The long-term goal of this project is to define dysfunctional molecular networks underlying the pathogenesis of Lewy body Dementia (LBD) disease, and the synergistic interaction of amyloid-beta and alpha-synuclein, primarily by omics-based systems biology approaches, focusing on proteomics and lipidomics using cutting- edge mass spectrometry (MS) in Project 2. LBD is the second most common cause of progressive dementia and shares characteristics with Alzheimer's disease (AD) and Parkinson's disease (PD). It is characterized by the manifestation of Lewy body (alpha-synuclein) pathology and amyloid plaques (amyloid-beta) in the brain. Clinically, LBD is associated with dementia, psychosis, and features of PD. Identifying clinically relevant molecules (DNAs, RNAs, proteins, or metabolites) is essential to predict, diagnose, treat, and prevent LBD. Complementary to the genome and transcriptome profiling in Project 1, Project 2 seeks to fully characterize the whole proteome, aggregated proteome, posttranslational modifications, and lipidome directly from well- characterized LBD and control brain specimens with different pathologies (provided by Core B). To achieve this goal, we have assembled a strong multidisciplinary team with established and renowned investigators in proteomics (Peng) and lipidomics (Han), both also having extensive expertise in studying neurodegeneration including analyzing human brain tissues. We will focus on three specific aims: (i) to identify aberrant protein networks in LBD with different pathologies by profiling the whole proteome; (ii) to integrate multiple-tier proteomics approaches to define LBD by profiling aggregated proteome, phosphoproteome and ubiquitinome; and (iii) to determine LBD pathways by lipidomics profiling. The acquired omics data will provide a rich resource for hypothesis-driven research, and will be integrated for generating a precise molecular signature shared in LBD cases, categorizing possible LBD subtypes, revealing key molecular dysfunction, especially linking the interaction of amyloid-beta and alpha-synuclein.

概括该项目的长期目标是定义功能障碍的分子网络，该分子网络为发病机理的发病机理。 Lewy身体痴呆（LBD）疾病，以及淀粉样蛋白β和α-突触核蛋白的协同相互作用，主要通过基于OMICS的系统生物学方法，专注于蛋白质组学和脂质组学，使用剪切 - 项目2中的边缘质谱法（MS）。LBD是进行性痴呆和与阿尔茨海默氏病（AD）和帕金森氏病（PD）共享特征。它以脑（α-突触核蛋白）病理学和淀粉样蛋白斑（淀粉样蛋白）的表现。在临床上，LBD与PD的痴呆，精神病和特征有关。识别临床上的相关分子（DNA，RNA，蛋白质或代谢产物）对于预测，诊断，治疗和预防LBD至关重要。项目1中的基因组和转录组分析的补充，项目2旨在完全表征直接从良好的表征具有不同病理的LBD和控制脑标本（由Core B提供）。实现这一目标目标，我们与一个既定且著名的调查员组成了一个强大的多学科团队蛋白质组学（PENG）和脂肪组学（HAN）都在研究神经退行性方面具有广泛的专业知识包括分析人脑组织。我们将重点关注三个特定目标：（i）识别异常蛋白通过分析整个蛋白质组，LBD中具有不同病理的网络；（ii）整合多层蛋白质组学方法是通过分析聚集的蛋白质组，磷蛋白质组和泛素组来定义LBD的方法；（iii）通过脂质组学分析确定LBD途径。获得的OMICS数据将提供丰富的资源用于假设驱动的研究，并将集成以生成LBD中共有的精确分子签名病例，分类可能的LBD亚型，揭示了关键的分子功能障碍，尤其是连接淀粉样蛋白β和α-核蛋白的相互作用。