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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种异质性神经退行性疾病， 在全球人群中流行，影响约4600万人。由于增加 长寿，患病率正在上升。AD的病理生理特征是细胞外β- 淀粉样沉积和细胞内过度磷酸化的tau蛋白。目前的AD药物 对疾病症状有一定的缓解作用，但并非对所有患者都有效， 观察效果。该疾病具有高度遗传性，具有复杂的分子基础， 大量的多基因成分。 迫切需要开发靶点发现和药物再利用的方法。 结合方法分析的进展，功能基因组学数据， 表型丰富的数据集可以成为识别新疗法的基础。我们的中央 一种假设是，一种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，并提供了一种强有力的方法 to drug药物target目标discovery发现.我们将开发尖端的基因锚定计算 AD药物再利用的方法，产生一个社区资源，以推进研究， AD疗法开发，利用协作（基础设施和机器学习） 与谷歌合作，并在AD的斑马鱼模型中进行目标验证。 我们聘请了一个跨学科的团队，以确保我们的成功和广泛的影响， 并为未来的创新研究奠定基础。

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.