The Microvascular Aging and Eicosanoids - Women's Evaluation of Systemic Aging Tenacity (MAE-WEST) ("You are never too old to become younger!") Specialized Center for Research Excellence (SCORE)

项目摘要- MAE-WEST评分总体 在整个生命周期中，女性的年龄与男性不同，最终导致女性在病态慢性疾病中占主导地位。 射血分数保留的心力衰竭、阿尔茨海默病和相关痴呆症等疾病，以及 慢性肾脏疾病。女性也更容易患多器官综合征（心脑、心肾） 往往比男人。多器官功能障碍的性别特异性差异的潜在机制仍然存在 不太了解。先前的研究表明，女性表现出加速的微血管老化， 与心脏、大脑和肾脏疾病有关。在这种情况下，全身性炎症已经成为一种 微血管功能障碍和这些慢性疾病状态发展的主要驱动因素。 我们小组的初步数据表明，类二十烷酸是一组多样的生物活性脂质， 系统性炎症的上游介质，可以影响内皮细胞功能，表现出性二型性 在循环血浆中，并且与某些血管表型相关。根据这些发现，我们假设， 局部和全身类二十烷酸变异的两性异形有助于微血管中的性别差异， 功能障碍，反过来，与年龄相关的多器官疾病的性别差异。受我们早期发现的启发 以及迫切需要了解年龄相关疾病中性别差异的决定因素和驱动因素 结果，我们建议建立微血管老化和类花生酸-妇女的评价系统 老化韧性（MAE-WEST）性别差异专业卓越研究中心（SCORE）。 利用我们的集体专业知识，我们计划推进对性别特异性分子驱动因素的理解， 慢性微血管和终末器官疾病通过3个基础项目。在项目1中，我们将研究 循环类花生酸水平的纵向变化与微血管年龄相关性改变的关系 2个大型社区队列中终末器官（心血管、神经认知、肾脏）疾病特征的功能。在 项目2，我们将前瞻性地招募一组女性和男性，并对其进行深入的表型分析，以评估 具有器官特异性和微血管疾病全球负担的类花生酸及其反应 一项使用FDA批准的药物（他汀类药物和ACEi/ARB）进行强化药物治疗的试验。最后，在项目3中， 我们将研究性别特异性类花生酸信号对人类内皮细胞功能的机制作用， 在器官特异性疾病的实验模型以及整个生物体衰老中的微血管功能。作为 作为SCORE的一个组成部分，我们将建立一个职业提升中心，提供强有力的培训 以及为受训人员和初级调查员提供指导。总的来说，这个高度协作和创新的SCORE 旨在改变我们对微血管和慢性多器官疾病的性别差异的理解， 反过来，通过跨学科的科学、教育和宣传，使有效的干预成为可能。 !

Project Abstract – MAE-WEST SCORE Overall Women age differently than men across the lifespan, culminating in a female predominance in morbid chronic diseases such as heart failure with preserved ejection fraction, Alzheimer’s disease and related dementias, and chronic kidney disease. Women also tend to develop multi-organ syndromes (heart-brain, heart-kidney) more frequently than men. The mechanisms underlying sex-specific differences in multi-organ dysfunction remain poorly understood. Prior work indicates that women exhibit accelerated microvascular aging, a process implicated in disorders of the heart, brain, and kidney. In this context, systemic inflammation has emerged as a primary driver of both microvascular dysfunction and the development of these chronic disease states. Preliminary data from our group indicates that eicosanoids, a diverse group of bioactive lipids that serve as the upstream mediators of systemic inflammation, can influence endothelial cell function, exhibit sexual dimorphism in circulating plasma, and are related to certain vascular phenotypes. Given these findings, we hypothesize that sexual dimorphism in both local and systemic eicosanoid variation contributes to sex differences in microvascular dysfunction and, in turn, to sex differences in age-related multi-organ disease. Motivated by our early findings and the critical need to understand the determinants and drivers of sex differences in age-related disease outcomes, we propose to create the Microvascular Aging and Eicosanoids –Women’s Evaluation of Systemic aging Tenacity (MAE-WEST) Specialized Center of Research Excellence (SCORE) on Sex Differences. Leveraging our collective expertise, we plan to advance the understanding of sex-specific molecular drivers of chronic microvascular and end-organ disease through 3 foundational projects. In Project 1, we will examine longitudinal variation in circulating eicosanoid levels in relation to age-related alterations in microvascular function in end-organ (cardiovascular, neurocognitive, renal) disease traits in 2 large community cohorts. In Project 2, we will prospectively enroll and deeply phenotype a cohort of women and men to assess the relation of eicosanoids with organ-specific as well as global burden of microvascular disease, as well as their response to a trial of intensive medical therapy with FDA-approved agents (statins and ACEi/ARB). Finally, in Project 3, we will study the mechanistic role of sex-specific eicosanoid signaling on human endothelial cell function and on microvascular function in experimental models of organ-specific disease as well as whole organism aging. As an integral part of this SCORE, we will establish a Career Enhancement Center that will provide robust training and mentorship for trainees and junior investigators. Collectively, this highly collaborative and innovative SCORE aims to transform our understanding of sex differences in microvascular and chronic multi-organ diseases and, in turn, enable effective interventions through inter-disciplinary science, education, and advocacy. !