Utilization of proteomics and lipidomics to identify modifiers of LBD

总结 该项目的长期目标是确定功能失调的分子网络的发病机制， 路易体痴呆（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， 主要是通过基于组学的系统生物学方法，专注于蛋白质组学和脂质组学，使用切割- 项目2中的边缘质谱（MS）。LBD是进行性痴呆的第二大常见原因， 与阿尔茨海默病（AD）和帕金森病（PD）具有相同的特征。其特点是 脑中路易体（α-突触核蛋白）病理学和淀粉样蛋白斑（淀粉样蛋白-β）的表现。 临床上，LBD与痴呆、精神病和PD特征相关。确定临床相关性 分子（DNA、RNA、蛋白质或代谢物）对于预测、诊断、治疗和预防LBD至关重要。 作为项目1中基因组和转录组分析的补充，项目2旨在全面表征 完整蛋白质组、聚集蛋白质组、翻译后修饰和脂质组直接来自孔- 表征的LBD和具有不同病理学的对照脑标本（由核心B提供）。实现这一 为了实现这一目标，我们组建了一支强大的多学科团队，其中包括知名的研究人员， 蛋白质组学（Peng）和脂质组学（Han），两者在研究神经变性方面也具有广泛的专业知识 包括分析人脑组织我们将集中在三个具体目标：（i）识别异常蛋白质 网络在LBD与不同的病理通过分析整个蛋白质组;（ii）整合多层 蛋白质组学方法通过分析聚集蛋白质组、磷酸化蛋白质组和泛素组来定义LBD; 和（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，并将被整合用于生成LBD中共享的精确分子特征 病例，对可能的LBD亚型进行分类，揭示关键的分子功能障碍，特别是将 淀粉样蛋白-β和α-突触核蛋白的相互作用。

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.