Molecular and Network Analyses of Lewy Body Dementia Pathogenesis

路易体痴呆发病机制的分子和网络分析

• 批准号: 10297518
• 负责人: Lih-Shen Chin
• 金额: $ 225.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297518
• 关键词: Accounting; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Animal Model; Antipsychotic Agents; Asparagine; Autopsy; Biochemical; Biological; Biological Markers; Brain; Cell physiology; Cell surface; Cells; Cellular Structures; Clinical; Coupled; Dementia; Dementia with Lewy Bodies; Diagnosis; Disease; Drug Targeting; Elderly; Functional disorder; Genomics; Glycoproteins; Golgi Apparatus; Human; Impaired cognition; Knowledge; Lewy Body Dementia; Lysosomes; Membrane; Membrane Proteins; Molecular; Molecular Abnormality; Molecular Analysis; Molecular Target; Motor; Nerve Degeneration; Neurobehavioral Manifestations; Organelles; Parkinson' s Dementia; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Polysaccharides; Post-Translational Protein Processing; Prevention; Protein Conformation; Proteins; Proteome; Proteomics; Research; Role; Science; Source; Study models; Symptoms; Syndrome; Technology; Therapeutic; Validation; base; biomarker development; brain tissue; case control; clinical Diagnosis; curative treatments; disease mechanisms study; experimental study; extracellular; follow-up; glycoproteomics; glycosylation; human disease; innovation; insight; motor symptom; multiple omics; neuropathology; neuropsychiatric symptom; novel; prevent; response; targeted biomarker; therapeutic development; trafficking; transcriptomics

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.

项目概要/摘要 路易体痴呆（LBD），包括帕金森病痴呆（PDD）和路易体痴呆 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% 痴呆症患者患有认知障碍、神经精神症状和 部分 LBD 患者患有帕金森运动症状，DLB 与 PDD 的临床区别在于。 基于任意定义的“一年规则”，以及DLB和PDD是否相同或不同的临床 我们目前对这些综合征的分子共性和差异的了解仍不清楚。 这两种 LBD 亚型的发病机制有限，而且由于诊断率低，LBD 的诊断率较低。 尽管如此，临床诊断标准的敏感性以及 LBD 与 AD 的临床区分面临的挑战。 LBD 和 AD 之间的临床症状有重叠，但 LBD 和 AD 之间存在关键差异 患者对抗精神病药物治疗的反应表型重叠的分子基础。 目前，LBD 和 AD 之间的差异尚不清楚，尚无可靠的 LBD 生物标志物。 诊断，并且没有有效的预防手段或疾病缓解治疗，强调需要 该项目将使用一种创新的综合方法，更好地了解 LBD 的发病机制。 蛋白质组学、糖蛋白质组学和糖组学与网络分析相结合，解决以下关键问题 问题：LBD 的两种亚型（PDD 和 LBD）有哪些分子异常？ DLB）具有相同或不同的分子异常？PDD 和 DLB 如何重叠或不同？ 分子水平上的AD？拟议的研究将确定人类疾病相关的变化 LBD 脑蛋白质组、糖蛋白质组和糖组，识别参与的分子靶点和通路 LBD 发病机制，并阐明与 LBD 相似或不同的致病机制 AD。各种生物化学、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 相关目标和 拟议研究的结果将增进我们对 LBD 发病机制的了解并提供帮助。 加快发现小黑肌和阿尔茨海默病的治疗方法。