Integrated multi-omics approach to identify early protein biomarkers in Alzheimer's disease and cognitive decline

摘要： K01提案的目的有两个：1)确定阿尔茨海默病(AD)的早期蛋白质生物标志物 和认知衰退；以及2)为艾莉森·福纳博士提供指导和资源，以追求 独立研究生涯使用多组学和纵向数据来改进预防和治疗 广告。在美国，每年有50万人被诊断为阿尔茨海默病。广告没有治愈的方法；从2002年到 2012年，几乎每一项新疗法的临床试验都失败了。血浆蛋白很容易按常规方法测定 护理，和蛋白质水平可能反映潜在的病理。一项新技术，可以快速检测数千种 大样本中的蛋白质有望促进蛋白质生物标记物的发现，并可能带来新的策略 用于早期风险分层和新的治疗方法。该建议利用了来自 心血管健康研究(CHS)，一项由NHLBI资助的5888名前瞻性人群队列研究 白人和非裔美国人男性和女性在20世纪90年代初应征入伍。可用的CHS数据包括血浆 1300个蛋白质的蛋白质水平数据，全基因组测序数据，年度认知评估包括 不同的功能结构域，AD的诊断信息，以及储存的生物样品。这项建议旨在1) 确定与AD发病时间和认知功能减退率相关的血浆蛋白；2)评估 支持和反对高信号蛋白在阿尔茨海默病和认知衰退中的因果作用的遗传证据；以及3) 评估血浆p-tau181浓度--AD病理的生物标记物--与随后的 阿尔茨海默病与认知功能减退的临床诊断这项拟议的研究不仅将增进我们对 但也可能识别AD的重要临床生物标记物和治疗靶点。福纳博士 是华盛顿大学流行病学系的助理教授。和她在一起 在基因组学和高维数据分析的背景下，福纳博士处于有利地位，可以实现这些目标 这项提议。她组建了一支经验丰富的协作式导师团队，并发展了一种 创新的培训计划，将帮助她实现研究独立。中国的研究和培训计划 这项提案将使福纳博士做好准备，通过使她能够建立 研究技能和领域专业知识，学习新的分析技术，建立富有成效的合作， 并生成初步数据。总而言之，在这个K01奖项的支持下，福纳博士可以发起一个 成功的职业发展战略，以预测、预防和治疗AD。

SUMMARY: The purpose of this K01 proposal is twofold: 1) to identify early protein biomarkers in Alzheimer’s disease (AD) and cognitive decline; and 2) to provide Alison Fohner, PhD with the mentorship and resources to pursue an independent research career using multi-omic and longitudinal data to improve prevention and treatment of AD. Every year, 500,000 people are diagnosed with AD in the US. AD has no cure; and between 2002 and 2012, nearly every clinical trial for new therapeutics failed. Plasma proteins are easily measured in routine care, and protein levels may reflect underlying pathology. New technology that rapidly assays thousands of proteins in large samples promises to improve protein biomarker discovery, and could lead to new strategies for early risk stratification and for novel therapeutics. This proposal leverages the extensive existing data from the Cardiovascular Health Study (CHS), an NHLBI-funded prospective population-based cohort study of 5888 White and African American men and women recruited in the early 1990s. Available CHS data include plasma protein level data on 1300 proteins, whole genome sequencing data, yearly cognitive assessments covering different functional domains, diagnostic information on AD, and stored biospecimens. This proposal aims 1) to identify plasma proteins associated with time-to-incident AD and with rate of cognitive decline; 2) to assess genetic evidence for and against causal roles of high-signal proteins in AD and cognitive decline; and 3) to estimate the association of plasma p-tau181 concentrations, a biomarker of AD pathology, with subsequent clinical diagnosis of AD and cognitive decline. This proposed research will not only advance our understanding of AD pathology, but may also identify important clinical biomarkers and therapeutic targets for AD. Dr. Fohner is an Assistant Professor in the Department of Epidemiology at the University of Washington. With her background in genomics and high-dimensional data analysis, Dr. Fohner is well-positioned to pursue the Aims of this proposal. She has composed an experienced and collaborative mentorship team, and has developed an innovative training plan that will help her achieve research independence. The research and training plans in this proposal will prepare Dr. Fohner to successfully compete for future R01 funding by enabling her to build research skills and domain expertise, to learn new analytical techniques, to forge productive collaborations, and to generate preliminary data. In summary, with the support of this K01 award, Dr. Fohner can launch a successful career developing strategies to predict, prevent, and treat AD.