MAE-WEST SCORE Project 1 Population

MAE-WEST SCORE 项目 1 人口

基本信息

批准号：
10198760
负责人：
Susan Cheng
金额：
$ 19.45万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10198760
关键词：
Acute Age Aging Alzheimer&apos s disease related dementia Anti-Inflammatory Agents Atherosclerosis Risk in Communities Biological Biological Aging Blood Vessels Brain Cardiology Cardiovascular system Centers of Research Excellence Chronic Chronic Disease Chronic Kidney Failure Chronology Clinical Communities Data Development Disease Disease Outcome EFRAC Eicosanoids Elderly Endothelium Epidemiologist Etiology Evaluation Exhibits Exposure to Failure Female Foundations Framingham Heart Study Functional disorder Geriatrics Goals Gonadal Steroid Hormones Heart Heart failure Hormonal Human Impaired cognition Incidence Individual Inflammation Inflammatory Inflammatory Response Infrastructure Investigation Kidney Life Cycle Stages Lipids Longevity Mass Spectrum Analysis Measures Mediating Mediation Mediator of activation protein Methods Microvascular Dysfunction Morbidity - disease rate Nature Nephrology Neurocognitive Organ Outcome Participant Patients Pattern Persons Physical Function Physical activity Plasma Population Population Sciences Predisposition Process Prognosis Public Health Renal function Reporting Request for Applications Resources Risk Risk Factors Role Sampling Sampling Studies Scientific Advances and Accomplishments Scientist Sex Differences Specialized Center Stress Structure System Techniques Thromboplastin Time Variant Vascular Diseases Woman Work age effect age related base clinical development cohort effective intervention experience follow-up frailty functional decline healthy aging heart function improved indexing male men microvascular aging mortality offspring older men older women population based preservation response sex sexual dimorphism small molecule stressor trait translational scientist vascular risk factor

项目摘要

Project Abstract – MAE-WEST SCORE Project 1 Over the course of life, chronic stressors contribute to multi-organ aging and dysfunction and, ultimately, the development of clinical disease. Sex remains a critical determinant of the nature and pace of aging and ultimately longevity. Among mammalian species, it is even more clear that females fundamentally age differently from males. With advancing chronologic age in humans, differences in biological aging between women and men become even more pronounced, culminating in the female predominance for a number of important morbid disease conditions, including notably Alzheimer’s disease and related dementias (ADRD), heart failure with preserved ejection fraction (HFpEF), progressive chronic kidney disease (CKD), and in turn systemic frailty. Mechanisms underlying the female predominance for these major morbidities remains unknown and are not explained by variations in sex hormones or survival bias. Our preliminary work supports a central hypothesis that sexual dimorphism in inflammatory eicosanoid mediators contribute to sex differences in microvascular dysfunction and, in turn, to sex differences in age-related multi-organ disease, including for ADRD, HFpEF and CKD. Elucidating a common pathophysiologic basis for the female predominance of ADRD, HFpEF, and CKD holds the key to effective interventions for reducing the excess burden of age-related disease in women. Motivated our findings and the critical need to understand the determinants and drivers of sex differences in major age-related disease outcomes, we propose to establish the Microvascular Aging and Eicosanoids – Women’s Evaluation of Systemic aging Tenacity (MAE-WEST) (“You are never too old to become younger!”) Specialized Center of Research Excellence (SCORE) on Sex Differences, in response to NIH RFA-OD-19-013. Our goal is to form a robust and sustainable structure of academic activities centered on systematically interrogating sex differences in the relationship among eicosanoids, microvascular dysfunction, and age-related end-organ disease, with an initial focus on the microvascular aging effects on brain, heart, and kidney function. This goal will be achieved by an outstanding collaborative team of clinician-scientists (with expertise in geriatrics, cardiology, and nephrology), epidemiologists, basic and translational scientists, analytical chemists, biostatisticians, and bioinformaticians. Leveraging our collective experience, resources, and infrastructure, we will advance the scientific enterprise through 3 foundational projects aligned and complementary yet independent. Project 1 will determine the sex-specific relations of eicosanoids with microvascular dysfunction and incidence of major end-organ disease outcomes in the community. This population science project will examine longitudinal variation in hundreds of circulating eicosanoids in relation to: (i) discrete measures of microvascular function; (ii) trajectories of multi-system (neurocognitive, cardiovascular, renal) as well as global functional decline; and, (iii) incidence of overt end-organ disease (ADRD, HFpEF, CKD) across aging women and men patient, in two independent community-based cohorts.

项目摘要 – MAE-WEST SCORE 项目 1 在生命过程中，慢性压力源会导致多器官衰老和功能障碍，并最终导致临床疾病的发展仍然是衰老的性质和速度的关键决定因素。在哺乳动物物种中，更明显的是，雌性的寿命与雌性的寿命根本不同。随着人类年龄的增长，女性和男性之间的生物衰老存在差异。变得更加明显，最终导致一些重要病态的女性占主导地位疾病状况，特别是阿尔茨海默氏病和相关痴呆症 (ADRD)、心力衰竭射血分数保留（HFpEF）、进行性慢性肾病（CKD）以及全身虚弱。这些主要疾病的女性占主导地位的机制仍然未知，也不清楚我们的初步工作支持一个中心假设：炎症类二十烷酸介质的性别二态性导致微血管的性别差异功能障碍，进而导致与年龄相关的多器官疾病的性别差异，包括 ADRD、HFpEF 和阐明 ADRD、HFpEF 和 CKD 女性占主导地位的共同病理生理学基础是采取有效干预措施减少妇女因年龄相关疾病而过度负担的关键。激发了我们的发现以及了解性别差异的决定因素和驱动因素的迫切需要与年龄相关的主要疾病结果，我们建议建立微血管衰老和类二十烷酸 – 女性系统衰老韧性评估（MAE-WEST）（“你永远不会变得更年轻！”）性别差异专业卓越研究中心 (SCORE)，响应 NIH RFA-OD-19-013。我们的目标是形成一个稳健且可持续的学术活动结构，以系统地为中心探讨类二十烷酸、微血管功能障碍和年龄相关性之间关系的性别差异终末器官疾病，最初关注微血管老化对大脑、心脏和肾脏功能的影响。这一目标将由杰出的临床医生科学家合作团队（具有老年病学、心脏病学和肾病学）、流行病学家、基础和转化科学家、分析化学家、我们利用生物统计学家和生物信息学家的集体经验、资源和基础设施。将通过 3 个相互协调且互补的基础项目推进科学事业项目 1 将确定类二十烷酸与微血管的性别特异性关系。社区主要终末器官疾病结果的功能障碍和发病率。科学项目将研究数百种循环类二十烷酸与以下方面的纵向变化：(i) 离散的微血管功能的测量；(ii) 多系统（神经认知、心血管、肾脏）的轨迹以及整体功能下降；(iii) 明显的终末器官疾病（ADRD、HFpEF、CKD）的发生率老年女性和男性患者，分为两个独立的社区队列。