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

总结： 这项K 01提案的目的有两个：1）鉴定阿尔茨海默病（AD）的早期蛋白质生物标志物 和认知能力下降; 2）为Alison Fohner博士提供导师和资源，以追求 利用多组学和纵向数据的独立研究生涯，以改善预防和治疗 AD.在美国，每年有50万人被诊断患有AD。AD没有治愈方法; 2002年至2009年期间， 2012年，几乎所有新疗法的临床试验都失败了。血浆蛋白很容易在常规中测量 护理和蛋白质水平可以反映潜在的病理。新技术可以快速分析数千种 大样本中的蛋白质有望改善蛋白质生物标志物的发现，并可能导致新的策略 用于早期风险分层和新疗法。该提案利用了来自 心血管健康研究（CHS），一项由NHLBI资助的前瞻性基于人群的队列研究， 白色和非洲裔美国人的男性和女性在20世纪90年代初招募。可用的CHS数据包括血浆 1300种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， 不同的功能域，AD的诊断信息和储存的生物标本。该建议旨在：（1） 鉴定与AD发病时间和认知能力下降率相关的血浆蛋白; 2）评估 支持和反对高信号蛋白在AD和认知能力下降中的因果作用的遗传学证据;以及3） 估计血浆p-tau 181浓度（AD病理学的生物标志物）与随后的 临床诊断为AD和认知能力下降。这项拟议中的研究不仅将推进我们对 AD病理学的研究，但也可以确定重要的临床生物标志物和AD的治疗靶点。弗纳博士 是华盛顿大学流行病学系的助理教授。和她 在基因组学和高维数据分析的背景下，Fohner博士处于有利地位，可以追求目标 这一提议。她组成了一个经验丰富和协作的导师团队，并制定了一个 创新的培训计划，这将有助于她实现研究独立。研究和培训计划， 该提案将使Fohner博士能够建立 研究技能和领域专长，学习新的分析技术，建立富有成效的合作， 并生成初步数据。总之，在K 01奖的支持下，Fohner博士可以推出一个 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.