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.

项目摘要 /摘要 Lewy身体痴呆（LBD），包括帕金森病痴呆症（PDD）和痴呆症 身体（DLB）是阿尔茨海默氏病（AD）相关痴呆的一种主要形式，占所有痴呆症的30％ 痴呆病例。 LBD患者患有认知障碍，神经精神症状和A LBD患者的一部分患有帕金森运动症状。 DLB与PDD的临床分化为 基于任意定义的“一年规则”，以及DLB和PDD是相同还是不同的临床 综合征仍然不清楚。我们目前对分子共同点和差异的了解 这两个LBD亚型的发病机理受到限制。此外，由于低的LBD，LBD的诊断不足 LBD临床诊断标准和AD临床分化方面的挑战的敏感性。尽管 LBD和AD之间的临床症状重叠，LBD和AD之间存在关键差异 对抗精神病药治疗的反应的患者。表型重叠的分子基础 LBD和AD之间的差异是未知的。目前，LBD没有可靠的生物标志物 诊断，没有有效的预防手段或修改疾病的治疗方法，强调了需要 更好地了解LBD的发病机理。该项目将使用整合的创新方法 蛋白质组学，糖蛋白质组学和糖果学以及网络分析以解决以下密钥 问题：定义LBD的分子异常是什么？执行两个LBD子类型（PDD和 DLB）具有相同或不同的分子异常？ PDD和DLB如何与或不同 AD在分子水平上？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酶，鉴定了涉及的分子靶标和途径 LBD发病机理，并阐明了与与或不同的LBD致病机制 广告。多种生化，细胞生物学，靶向糖蛋白质组学和功能分析以及 将进行动物模型研究以验证和研究确定的LBD相关靶标和 途径。拟议研究的发现将提高我们对LBD发病机理的了解并有助于 加快努力发现LBD和AD治疗疗法的努力。