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

综合多组学方法识别阿尔茨海默病和认知能力下降的早期蛋白质生物标志物

• 批准号: 10560601
• 负责人: Alison Elizabeth Fohner
• 金额: $ 12.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560601
• 关键词: Affect; African American; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Area; Award; Biological Assay; Biological Process; Biology; Brain; Cerebrospinal Fluid; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Cohort Studies; Collaborations; Cross-Sectional Studies; Data; Data Analyses; Development Plans; Diagnosis; Diagnostic; Disease Outcome; Doctor of Philosophy; Drug Targeting; Early identification; Elderly; Epidemiology; Etiology; Framingham Heart Study; Funding; Future; Genetic; Genomics; Goals; Grant; Health; Immune; Impaired cognition; Individual; Jackson Heart Study; Learning; Measures; Mendelian randomization; Mentored Research Scientist Development Award; Mentorship; Methods; National Heart, Lung, and Blood Institute; Nerve Degeneration; Outcome; Participant; Pathology; Pathway interactions; Persons; Plasma; Plasma Proteins; Populations at Risk; Positioning Attribute; Prevention; Productivity; Protein Analysis; Proteins; Proteomics; Public Health; Research; Research Design; Research Personnel; Resources; Risk; Role; Sampling; Signaling Protein; Techniques; Time; Training; Universities; Washington; Woman; adjudication; biomarker discovery; brain magnetic resonance imaging; cardiovascular health; career; career development; caucasian American; cerebral atrophy; clinical biomarkers; clinical diagnosis; cognitive testing; design; experience; forging; genome sequencing; genome wide association study; genomic data; high dimensionality; improved; innovation; instrument; longitudinal analysis; men; multidimensional data; multiple omics; neuroinflammation; new technology; new therapeutic target; novel; novel marker; novel therapeutics; population based; prevent; professor; prospective; protein biomarkers; rapid test; recruit; risk stratification; routine care; skills; targeted treatment; tau Proteins; therapeutic target; whole genome

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.

概括： K01 提案的目的有两个：1) 识别阿尔茨海默病 (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善预防和治疗 2002 年至 2002 年，美国每年有 50 万人被诊断患有 AD。 2012 年，几乎所有新疗法的临床试验都失败了。血浆蛋白的常规测量很容易。 护理和蛋白质水平可能反映潜在的病理学，可快速检测数千种疾病。 大样本中的蛋白质有望改善蛋白质生物标志物的发现，并可能带来新的策略 该提案利用了广泛的现有数据。 心血管健康研究 (CHS)，这是一项由 NHLBI 资助的基于人群的前瞻性队列研究，研究对象为 5888 人 20 世纪 90 年代初招募的白人和非裔美国男性和女性的可用 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、年度认知评估涵盖 不同的功能域、AD 诊断信息和存储的生物样本该提案的目的是 1) 确定与 AD 发病时间和认知能力下降率相关的血浆蛋白 2) 进行评估； 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证据；以及 3) 估计血浆 p-tau181 浓度（AD 病理学的生物标志物）与随后的相关性 AD 和认知能力下降的临床诊断。这项研究不仅将增进我们的理解。 Fohner 博士表示，该研究不仅可以帮助确定 AD 病理学的重要临床生物标志物和治疗靶点。 是华盛顿大学流行病学系的助理教授。 Fohner 博士拥有基因组学和高维数据分析背景，有能力实现这一目标 她组建了一支经验丰富且协作的指导团队，并开发了一个 创新的培训计划将帮助她实现研究独立性。 该提案将使 Fohner 博士能够成功地竞争未来的 R01 资金，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， 总而言之，在这个 K01 奖项的支持下，Fohner 博士可以发起一项研究。 预测、预防和治疗 AD 的成功职业发展策略。