Utilization of proteomics and lipidomics to identify modifiers of LBD

摘要 这一项目的长期目标是定义在糖尿病发病机制下的功能失调的分子网络 路易体痴呆(LBD)，以及淀粉样β蛋白和α-突触核蛋白的协同作用， 主要是以组学为基础的系统生物学方法，重点是蛋白质组学和脂类组学使用切割- LBD是进展性痴呆症的第二大常见原因， 与阿尔茨海默病(AD)和帕金森病(PD)具有相同的特征。它的特点是 路易体(α-突触核蛋白)病理和脑内淀粉样斑块(淀粉样β-蛋白)的表现。 在临床上，LBD与痴呆症、精神病和帕金森病的特征有关。确定临床相关性 分子(DNA、RNA、蛋白质或代谢物)对预测、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试图充分描述 完整的蛋白质组，聚集的蛋白质组，翻译后修饰，和直接从井- 具有不同病理特征的LBD和对照脑标本(由Core B提供)。要做到这一点 Goal，我们组建了一支强大的多学科团队，拥有成熟和知名的研究人员 蛋白质组学(Peng)和脂质组学(HAN)，都在研究神经退行性变方面拥有广泛的专业知识 包括分析人脑组织。我们将集中于三个具体的目标：(I)鉴定异常蛋白 通过对整个蛋白质组的描述，在LBD中构建不同病理的网络；(Ii)整合多层 蛋白质组学方法通过对聚集蛋白质组、磷酸蛋白质组和泛素组谱进行分析来定义LBD； 以及(Iii)通过脂质组学分析来确定LBD途径。获得的组学数据将提供丰富的资源 用于假设驱动的研究，并将被集成以生成在LBD中共享的精确分子签名 病例，对可能的LBD亚型进行分类，揭示关键的分子功能障碍，特别是与 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.