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.

项目摘要/摘要 迄今为止，还没有有效的认知障碍和痴呆症治疗方法。了解机制 促进认知的韧性和延迟血管性痴呆，特别是在高风险人群中，是一个 延长认知健康跨度的免费方法。缺血性中风存活代表增长 美国老年人的人口以及阿尔茨海默氏病的非常高风险的人群 痴呆症（ADRD）。除了脑梗塞，生物因子和分子的潜在燃烧之外 引起中风后认知韧性和痴呆发作时间差异的机制，仍然存在 不清楚。物理水平的生物老化过程与年龄相关疾病的风险有关 包括认知，中风和痴呆症。但是，如果生物学上的差异是否存在，仍然很糟糕 中风后ADRD的衰老解释变化。在分子水平上，公认的衰老生物学 机制，蛋白质作为蛋白质控制细胞功能起着核心作用，可以帮助识别新颖 治疗靶标，与衰老中的认知轨迹有关。但是，这些关联是 仅限于验尸后评估，尚未在可访问的组织（例如外围组织）中进行评估 血液和弱势群体（例如缺血性中风存活）。直接目的 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 缺血性中风存活中血管性痴呆发作的时机。我将测量生物衰老 使用心血管健康研究（CHS）中的血液测试收集的物理生物标志物数据和 鹿特丹研究（RS）。然后，我将将这些表型与最先进的临床确定相结合 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 中风后的弹性。我将利用一个基于合并的蛋白质组学平台来识别分子网络和 中风幸存者中生物衰老，认知弹性和血管痴呆的细胞水平途径 和健康对照。我将评估合并生物学衰老，蛋白质组学和临床中风数据的算法 用于使用监督机的认知弹性和特定领域的认知结果的预后 学习。我非常适合根据1）我先前在流行病学方面的研究经验 中风和衰老，2）确保这项研究最高质量的杰出心理团队； 3） 卓越的研究环境，以支持我的职业发展。拟议的培训和研究将 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 在分子流行病学与ADRD的交集中建立独立职业 脆弱的人群。该项目将使生物学和分子的前所未有的观点能够 认知弹性的机制，可揭示新的生物标志物和治疗靶标的来保护认知 缺血性中风存活的老年健康。