Discovery of Novel Proteomic Targets for Treatment of Alzheimer's Disease

发现治疗阿尔茨海默病的新蛋白质组靶点

• 批准号: 9339811
• 负责人: DAVID ALAN BENNETT
• 金额: $ 16.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339811
• 关键词: Adult; Aging; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Asses; Autopsy; Baltimore; Biochemical; Bioinformatics; Biological Models; Biology; Brain; Brain region; Cell Culture Techniques; Cell Nucleus; Cell model; Cell physiology; Clinic; Cognition; Cognitive; Cognitive aging; Communities; Data; Dementia; Disease; Drosophila genus; Drug Targeting; Early Diagnosis; Early Intervention; Early treatment; Environment; Epidemic; Epigenetic Process; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Goals; Health; Human; Impaired cognition; Intercept; Linear Regressions; Link; Longitudinal Studies; Mass Spectrum Analysis; Mediating; Memory; Methods; Modeling; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Other Genetics; Pathogenesis; Pathologic; Pathological Staging; Pathology; Pathway interactions; Phase; Play; Post-Translational Protein Processing; Prevention; Process; Proteins; Proteome; Proteomics; RNA Splicing; Reaction; Religion and Spirituality; Resources; Risk Factors; Role; Series; Staging; Structure; Synapses; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Validation; advanced system; age effect; base; cell type; clinically relevant; cognitive change; cohort; differential expression; drug development; drug discovery; effective therapy; genetic manipulation; innovation; link protein; mild cognitive impairment; mouse model; non-demented; novel; protein aggregate; targeted treatment; tau Proteins; therapeutic target

DESCRIPTION (provided by applicant): This proposal uses proteomics to better understand Alzheimer's disease pathogenesis with a large-scale, unbiased, and direct approach to discover and validate novel disease processes in postmortem AD brain, and to prioritize new targets for early stage therapeutic intervention. The AD proteome mediates the effects of aging, genetics and other risk factors and contains unidentified protein targets for therapies. The approach leverages the strengths of a national team of collaborating AD Centers and associated studies of aging, an innovative proteomics platform, advanced systems biology, and model systems to produce new treatment targets. The first aim will identify novel proteomic targets selectively altered in asymptomatic AD brain. Brains will be analyzed by mass spectrometry (MS), yielding discovery proteomes to compare 1) controls free of AD and other pathologies; 2) asymptomatic controls with AD pathology; 3) non-demented mildly impaired cases with AD pathology, 4) definite AD, and 5) other neurodegenerative diseases. Protein changes in synapses, insoluble aggregates, glial and neuron-specific nuclei, and select posttranslational modifications will be determined. Bioinformatics will be used with available large-scale data to identify potentially druggable targets in key networks and cellular processes. The second aim will validate candidate proteomic targets in postmortem brains from independent community and clinic-based cohorts and determine relationships with clinicopathological features, including cognition. Absolute levels of candidate proteins will be quantified using selected reaction monitoring MS. The third aim will establish links between the validated proteome and AD pathogenesis and druggability. The most promising candidates will be studied for effects on neuronal viability and interactions with Ass and tau using cell culture and drosophila models. These results and other data will drive selection of the most promising candidates to advance to mouse models to assess therapeutic potential.

描述（由申请人提供）：该提案使用蛋白质组学更好地了解阿尔茨海默氏病发病机理，并采用大规模，公正和直接方法来发现和验证验尸大脑中的新型疾病过程，并优先考虑早期治疗干预的新目标。 AD蛋白质组介导衰老，遗传学和其他危险因素的影响，并含有未鉴定的疗法蛋白靶标。该方法利用了一个由合作的广告中心和相关衰老研究的国家团队的优势，创新的蛋白质组学平台，先进的系统生物学和模型系统，以产生新的治疗目标。第一个目的将在无症状AD大脑中选择性改变新颖的蛋白质组学靶标。大脑将通过质谱法（MS）分析，产生发现蛋白质组以比较1）没有AD和其他病理的控制； 2）具有AD病理学的无症状对照； 3）非痴呆的轻度损害病例患有AD病理学，4）明确的AD和5）其他神经退行性疾病。将确定突触，不溶性聚集体，神经胶和神经元特异性核的蛋白质变化以及选择后翻译后修饰。生物信息学将与可用的大规模数据一起使用，以识别关键网络和细胞过程中的潜在可药物目标。第二个目标将验证来自独立社区和基于诊所的同类术后大脑中的候选蛋白质组学靶标，并确定与临床病理学特征（包括认知）的关系。将使用选定的反应监测MS来量化候选蛋白的绝对水平。第三个目标将建立经过验证的蛋白质组与AD发病机理和药物可药物之间的联系。将研究最有希望的候选人，以使用细胞培养和果蝇模型对神经元的生存能力以及与Ass和Tau的相互作用。这些结果和其他数据将推动最有前途的候选人的选择，以提高小鼠模型以评估治疗潜力。