Molecular and Network Analyses of Lewy Body Dementia Pathogenesis

项目摘要/摘要 路易体痴呆(LBD)，包括帕金森病痴呆(PDD)和路易痴呆症 身体(DLB)，是阿尔茨海默病(AD)相关痴呆的一种主要形式，占所有痴呆的30% 痴呆症病例。LBD患者有认知障碍、神经精神症状和 部分LBD患者有帕金森氏运动症状。DLB与PDD的临床鉴别 基于任意定义的一年规则，以及DLB和PDD是相同的还是不同的临床 症状仍不清楚。我们目前对分子的共性和差异的认识 这两种LBD亚型的发病机制有限。此外，由于LBD的低诊断，LBD被低估了 临床诊断标准的敏感性和临床鉴别LBD和AD的挑战。尽管 LBD和AD在临床症状上的重叠，LBD和AD有关键的区别 患者对抗精神病药物治疗的反应。表型重叠的分子基础 LBD和AD之间的不同之处尚不清楚。目前，LBD尚无可靠的生物标志物。 诊断和没有有效的预防或治疗手段，突出需要 更好地了解LBD的发病机制。该项目将使用一种创新的方法，综合 蛋白质组学、糖蛋白组学和糖组学与网络分析相结合以解决以下关键问题 问题：定义LBD的分子异常是什么？两个LBD子类型(PDD和 具有相同或不同的分子异常？PDD和DLB与之有何重叠或不同之处 在分子水平上的AD？这项拟议的研究将确定人类与疾病相关的变化。 LBD脑蛋白质组、糖蛋白质组和糖蛋白，识别参与 LBD的发病机制，并阐明与LBD相似或不同的致病机制 广告。各种生化、细胞生物学、靶向糖蛋白组学和功能分析以及 将进行动物模型研究，以验证和研究已确定的LBD相关靶点和 小路。这项拟议研究的结果将促进我们对LBD发病机制的了解，并有助于 加快发现LBD和AD的根治疗法。

Project Summary / Abstract Lewy body dementia (LBD), which includes Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), is a major form of Alzheimer disease (AD)-related dementia, accounting for up to 30% of all dementia cases. Patients with LBD suffer from cognitive impairment, neuropsychiatric symptoms, and a fraction of LBD patients have Parkinsonian motor symptoms. Clinical differentiation of DLB from PDD is based on an arbitrarily defined “one-year rule”, and whether DLB and PDD are the same or different clinical syndromes remains unclear. Our current knowledge of the molecular commonalities and differences in the pathogenesis of these two LBD subtypes is limited. Furthermore, LBD is underdiagnosed, due to the low sensitivity of the clinical diagnosis criteria and challenges in clinical differentiation of LBD from AD. Despite the overlap in clinical symptoms between LBD and AD, there are key differences between LBD and AD patients in the responses to antipsychotic drug treatment. The molecular basis of the phenotypic overlaps and dissimilarities between LBD and AD is unknown. Currently, there is no reliable biomarker for LBD diagnosis and no effective means of prevention or disease-modifying treatment, highlighting the need to better understand the pathogenesis of LBD. This project will use an innovative approach of integrative proteomics, glycoproteomics, and glycomics coupled with network analyses to address the following key questions: What are the molecular abnormalities that define LBD? Do the two LBD subtypes (PDD and DLB) have the same or different molecular abnormalities? How do PDD and DLB overlap with or differ from AD at the molecular level? The proposed research will determine disease-associated changes in human LBD brain proteome, glycoproteome, and glycome, identify molecular targets and pathways involved in LBD pathogenesis, and elucidate LBD pathogenic mechanisms that are similar to or distinct from those of AD. A variety of biochemical, cell biological, targeted glycoproteomics, and functional analyses as well as animal model studies will be performed to validate and study the identified LBD-associated targets and pathways. Findings from the proposed research will advance our knowledge of LBD pathogenesis and help accelerate the effort to discover curative therapies for LBD as well as AD.