Advancing drug repositioning and development for Alzheimer's Disease using functional genomics and computational phenomics

利用功能基因组学和计算表型组学推进阿尔茨海默病的药物重新定位和开发

• 批准号: 10459749
• 负责人: Eric R Gamazon
• 金额: $ 75.6万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459749
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Animal Model; Atlases; Biological; Catalogs; Clinical Data; Collaborations; Communities; Complex; Computer software; Computing Methodologies; Data Set; Development; Disease; Drug Targeting; Ensure; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Heritability; Human; Immune; Individual; Infrastructure; Liver; Longevity; Machine Learning; Maps; Meta-Analysis; Methodology; Microglia; Modeling; Molecular; Neurodegenerative Disorders; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Population; Prevalence; Proxy; Recording of previous events; Research; Resources; Role; Single Nucleotide Polymorphism; Spleen; Symptoms; Tissues; Untranslated RNA; Validation; Variant; Whole Blood; Zebrafish; abeta deposition; advanced analytics; biobank; brain cell; causal variant; clinical Diagnosis; comorbidity; differential expression; drug development; drug repurposing; extracellular; functional genomics; genetic risk factor; genome wide association study; genomic data; genomic locus; human disease; hyperphosphorylated tau; improved; innovation; insight; network models; new therapeutic target; novel therapeutics; open source; phenome; phenomics; programs; public health relevance; side effect; success; therapeutic development; trait; transcriptome

PROJECT SUMMARY Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder which is highly prevalent in the global population, affecting around 46 million individuals. Due to increased longevity, the prevalence is rising. AD is characterized pathophysiologically by extracellular β- amyloid deposition and intracellular hyperphosphorylated tau. Current medications for AD provide some relief from disease symptoms but are not effective in all patients while severe side effects are observed. The disease is highly heritable and has a complex molecular basis, with a substantial polygenic component. There is an urgent need for developing approaches to target discovery and drug repurposing. The combination of methodological analytic advances, functional genomics data, and phenotype-rich datasets can be the foundation for identifying new therapies. Our central hypothesis is that an integrative approach spanning human phenomics and genomics will offer new AD therapeutic possibilities, including drug repositioning, and provide a powerful approach to drug target discovery. We will develop cutting-edge genetics-anchored computational methodologies for AD drug repurposing, generate a community resource to advance research in AD therapeutics development, leverage a collaboration (infrastructure and machine learning) with Google, and conduct target validation in a zebrafish model of AD. We have engaged an interdisciplinary team to ensure the success and broad impact of our proposal and lay the groundwork for future innovative research.

项目摘要 阿尔茨海默氏病（AD）是一种异质性神经退行性疾病，高度高 在全球人口中，由于增加了4600万人 长期，患病率正在上升。 淀粉样蛋白沉积的腹地腹地tau。 减轻疾病症状的缓解 观察到这种疾病是高度遗传的，具有复杂的分子基础 实质性多基因组件。 开发针对发现和药物再证明的方法有一个紧迫的数字。 方法论分析进步，功能基因组学数据以及 富含表型的数据集可以是识别我们的中心的基础 假设是跨越人类现象学和基因组学的综合方法将提供 新的广告治疗可能性，包括药物重新定位并提供强大的方法 对药物的发现。 广告药物再利用的方法论，生成社区资源，以提高研究 广告疗法开发，利用协作（基础架构和机器学习） 使用Google，并在AD的斑马鱼模型中进行目标验证。 我们有英语和国际团队对我们的成功和广泛影响 提案并为未来的创新研究奠定了基础。