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: 10480887
• 负责人: Eric R Gamazon
• 金额: $ 73.4万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480887
• 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; gene network; 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.

项目概要 阿尔茨海默病（AD）是一种异质性神经退行性疾病，发病率很高 在全球人口中普遍存在，影响约 4600 万人。由于增加 随着寿命的延长，患病率不断上升。 AD 的病理生理学特征是细胞外 β- 淀粉样蛋白沉积和细胞内过度磷酸化的 tau 蛋白。目前治疗 AD 的药物 可以在一定程度上缓解疾病症状，但并非对所有患者都有效，同时严重副作用 观察到效果。该疾病具有高度遗传性，具有复杂的分子基础， 显着的多基因成分。 迫切需要开发靶标发现和药物再利用的方法。 方法学分析进展、功能基因组学数据和 丰富表型的数据集可以成为识别新疗法的基础。我们的中央 假设跨越人类表型组学和基因组学的综合方法将提供 新的 AD 治疗可能性，包括药物重新定位，并提供了一种强大的方法 药物靶点发现。我们将开发尖端的遗传学锚定计算 AD 药物再利用的方法论，生成社区资源来推进研究 AD 疗法开发，利用协作（基础设施和机器学习） 与 Google 合作，并在 AD 的斑马鱼模型中进行目标验证。 我们聘请了一支跨学科团队来确保我们的项目取得成功并产生广泛影响 提出建议，为未来的创新研究奠定基础。

项目成果

The association between trauma exposure, polygenic risk and individual depression symptoms.

创伤暴露、多基因风险和个体抑郁症状之间的关联。

• DOI: 10.1016/j.psychres.2023.115101
• 发表时间: 2023
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Thorp,JacksonG;Gerring,ZacharyF;Colodro-Conde,Lucía;Byrne,EndaM;Medland,SarahE;Middeldorp,ChristelM;Derks,EskeM
• 通讯作者: Derks,EskeM