Biological Aging, the Proteome and Cognitive Resilience among Ischemic Stroke Survivors

缺血性中风幸存者的生物衰老、蛋白质组和认知弹性

• 批准号: 10661332
• 负责人: Reem Waziry
• 金额: $ 13.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661332
• 关键词: Age; Aging; Algorithms; Alzheimer' s disease related dementia; Area; Autopsy; Biological; Biological Aging; Biological Factors; Biological Markers; Biology of Aging; Blood; Blood Tests; Brain Infarction; Cell physiology; Chronology; Circulation; Clinical; Clinical assessments; Cognition; Cognitive; Cognitive Therapy; Data; Dementia; Detection; Disease; Elderly; Ensure; Environment; Epidemiology; Exhibits; Goals; Health; Impaired cognition; Individual; Infarction; Inflammatory; Ischemia; Ischemic Stroke; Machine Learning; Measures; Medical; Mentors; Molecular; Molecular Epidemiology; Monitor; Outcome; Outcome Measure; Pathway interactions; Peripheral; Phenotype; Physiological; Plasma; Play; Population; Primary Prevention; Process; Prognosis; Proteins; Proteome; Proteomics; Research; Research Personnel; Risk; Role; Sampling; Societies; Specificity; Stroke; System; Technology; Testing; Tissues; Training; Translating; Vascular Dementia; Vulnerable Populations; age related; aptamer; beta amyloid pathology; biomarker discovery; cardiovascular health; career; career development; cognitive change; cognitive function; cohort; cytokine; effective therapy; epidemiology study; experience; follow-up; healthspan; high risk population; high throughput analysis; human old age (65+); human tissue; improved; multidimensional data; multiple omics; new therapeutic target; novel marker; peripheral blood; post stroke; post stroke dementia; preservation; prognostic value; proteomic signature; resilience; response; skills; stressor; stroke outcome; stroke survivor; supervised learning; targeted treatment; tau Proteins

Project Summary/Abstract To date, there is no effective treatment for cognitive impairment and dementia. Understanding mechanisms that promote cognitive resilience and delay vascular dementia, particularly in high-risk populations, is a complimentary approach to extend cognitive health span. Ischemic stroke survivors represent a growing population among older adults in the U.S. and a very high-risk group for Alzheimer’s disease and related dementias (ADRD). Beyond the underlying burden of brain infarction, biological factors and molecular mechanisms that elicit differences in cognitive resilience and timing of dementia onset after stroke, remain unclear. Biological aging processes at the physiological level are associated with risk of age-related diseases including cognition, stroke and dementia. However, it remains poorly understood if differences in biological aging explain variabilities in post-stroke ADRD. At the molecular level, among recognized aging biology mechanisms, the proteome plays a central role as proteins control cell functions, can help identify novel therapeutic targets and are associated with cognitive trajectories in aging. However, these associations were restricted to post-mortem assessments and have not been assessed in accessible tissue such as peripheral blood and in vulnerable populations such as ischemic stroke survivors. The immediate objective of this application is to assess the role of biological aging and molecular proteomic mechanisms in cognitive resilience and timing of onset of vascular dementia among ischemic stroke survivors. I will measure biological aging using physiological biomarkers data collected from blood tests in the Cardiovascular Health Study (CHS) and the Rotterdam Study (RS). I will then integrate these phenotypes with state-of-the art clinical ascertainment of stroke and cognition over >15 years of follow-up to assess the role of biological aging differences in cognitive resilience after stroke. I will leverage an Aptamer-based proteomic platform to identify molecular networks and cellular-level pathways of biological aging, cognitive resilience and vascular dementia among stroke survivors and healthy controls. I will evaluate algorithms of combined biological aging, proteomic and clinical stroke data for prognosis of cognitive resilience and domain-specific cognitive outcomes using supervised machine learning. I am well suited to perform this research based on 1) my prior research experience in epidemiology of stroke and aging, 2) the outstanding mentoring team to ensure this research is of highest quality; and 3) the exceptional research environment to support my career development. The proposed training and research will help me acquire substantive new skills in molecular epidemiology, high-dimensional data and machine learning to establish an independent career as a researcher at the intersection of molecular epidemiology and ADRD in vulnerable populations. This project will enable unprecedented perspectives on biological and molecular mechanisms of cognitive resilience to uncover novel biomarkers and therapeutic targets to protect cognitive health in old age among ischemic stroke survivors.

项目概要/摘要 迄今为止，尚无有效的治疗认知障碍和痴呆的机制。 促进认知弹性并延缓血管性痴呆，特别是在高危人群中，是一种 延长认知健康寿命的补充方法代表了越来越多的缺血性中风幸存者。 美国老年人口和阿尔茨海默病及相关疾病的高危人群 痴呆症（ADRD）除了脑梗塞、生物因素和分子的潜在负担之外。 中风后引起认知弹性和痴呆发作时间差异的机制仍然存在 生理层面的生物衰老过程与年龄相关疾病的风险有关。 包括认知、中风和痴呆症。然而，人们对生物学差异是否存在了解仍然知之甚少。 在公认的衰老生物学中，衰老在分子水平上解释了中风后 ADRD 的变量。 机制中，蛋白质组在蛋白质控制细胞功能方面发挥着核心作用，可以帮助识别新的 治疗目标并与衰老的认知轨迹相关。 仅限于死后评估，尚未在可触及的组织（例如外周组织）中进行评估 血液和弱势群体（例如缺血性中风幸存者）的直接目标。 应用是评估生物衰老和分子蛋白质组学机制在认知弹性中的作用 以及缺血性中风幸存者血管性痴呆的发病时间 我将测量生物衰老。 使用从心血管健康研究 (CHS) 中的血液测试中收集的生理生物标志物数据，以及 然后我将把这些表型与最先进的临床确定结合起来。 中风和认知超过 15 年的随访，以评估生物衰老差异在认知中的作用 我将利用基于适体的蛋白质组平台来识别分子网络和 中风幸存者生物衰老、认知弹性和血管性痴呆的细胞水平途径 我将评估生物衰老、蛋白质组学和临床中风数据的组合算法。 使用监督机器预测认知弹性和特定领域的认知结果 我非常适合基于 1) 我之前在流行病学方面的研究经验来进行这项研究。 中风和衰老，2）优秀的指导团队确保这项研究具有最高的质量；3） 卓越的研究环境支持我的职业发展。 帮助我获得分子流行病学、高维数据和机器学习方面的实质性新技能 在分子流行病学和 ADRD 交叉领域建立独立的研究生涯 该项目将为弱势群体提供前所未有的生物学和分子视角。 认知弹性机制发现新的生物标志物和保护认知的治疗靶点 缺血性中风幸存者的老年健康。