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总分 在一生中，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 疾病，如射血分数保留的心力衰竭、阿尔茨海默病和相关的痴呆，以及 慢性肾脏疾病。女性也更容易患上多器官综合征(心-脑、心-肾)。 比男人更频繁。多器官功能障碍的性别差异背后的机制仍然存在 人们对此知之甚少。先前的研究表明，女性表现出微血管加速衰老的过程 与心脏、大脑和肾脏的紊乱有关。在这种背景下，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力。 来自我们小组的初步数据表明，二十烷类化合物是一种不同的生物活性脂类，作为 全身性炎症的上游介质，可影响内皮细胞功能，表现出性别二型性 在循环血浆中，并与某些血管表型有关。考虑到这些发现，我们假设 局部和全身二十烷类物质变异中的性别二型性导致微血管中的性别差异 功能障碍，进而导致与年龄相关的多器官疾病的性别差异。受我们早期发现的激励 以及了解年龄相关疾病中性别差异的决定因素和驱动因素的迫切需要 结果，我们建议创建微血管老化和二十烷类化合物-女性对全身性的评估 老龄化韧性(Mae-West)性别差异专业研究卓越中心(SCORE)。 利用我们的集体专业知识，我们计划推进对性别特定的分子驱动因素的理解 通过3个基础项目开展慢性微血管和终末器官疾病。在项目1中，我们将检查 循环二十烷类化合物水平的纵向变化与年龄相关的微血管改变 2个大型社区队列中的终末器官(心血管、神经认知、肾脏)疾病特征的功能。在……里面 项目2，我们将前瞻性地招募和深入表型一组女性和男性来评估这种关系 二十烷类化合物与器官特异性和全球微血管疾病负担及其反应 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二十烷酸信号在人类内皮细胞功能和其他方面的机制作用 器官特异性疾病实验模型中的微血管功能以及整个生物体的衰老。AS 作为这个分数不可分割的一部分，我们将建立一个职业提升中心，提供强有力的培训 并为受训人员和初级调查人员提供指导。总体而言，这一高度协作和创新的分数 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，实现有效的干预。 好了！

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. !