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)

微血管老化和类二十烷酸 - 女性全身老化韧性评估 (MAE-WEST)（“你永远不会太老，变得更年轻！”）卓越研究专业中心 (SCORE)

• 批准号: 10198755
• 负责人: Cathleen Noel Bairey Merz
• 金额: $ 167.02万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 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/10198755
• 关键词: Address; Advocacy; Age; Aging; Alzheimer' s disease related dementia; Awareness; Basic Science; Bioinformatics; Biological; Blood Vessels; Brain; Brain Diseases; Cardiology; Cardiovascular system; Cell physiology; Centers of Research Excellence; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical Sciences; Communities; Data; Development; Disease; Disease Outcome; EFRAC; Education; Eicosanoids; Endothelial Cells; Enrollment; Epidemiologist; Evaluation; Exhibits; Experimental Models; FDA approved; Female; Foundations; Functional disorder; Funding; Geriatrics; Goals; Health; Heart; Heart Diseases; Heart failure; Human; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Infrastructure; Kidney; Kidney Diseases; Leadership; Life Cycle Stages; Lipids; Longevity; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Microvascular Dysfunction; Molecular; Nature; Nephrology; Neurocognitive; Organ; Organ Model; Organism; Outcome; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Population Sciences; Positioning Attribute; Process; Receptor Activation; Renal function; Request for Applications; Research; Research Personnel; Research Project Grants; Resources; Role; Sampling; Scientific Advances and Accomplishments; Scientist; Secure; Sex Differences; Signal Transduction; Specialized Center; Structure; Syndrome; Therapeutic; Training; Variant; Whole Organism; Woman; Women' s Health; Work; age effect; age related; base; body system; burden of illness; career; clinical development; clinical phenotype; cohort; effective intervention; experience; forward genetics; frailty; functional decline; healthspan; heart function; improved; innovation; insight; male; men; microvascular aging; multidisciplinary; next generation; novel therapeutic intervention; operation; preservation; programs; prospective; receptor; response; science education; sex; sex disparity; sexual dimorphism; stressor; systemic inflammatory response; trait; translational scientist

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. !

项目摘要 - MAE-West分数总体 女性的年龄与整个生命周期的男性不同，在病态慢性病中以女性优势达到顶峰 诸如心力衰竭和保留的射血分数，阿尔茨海默氏病和相关痴呆症等疾病以及 慢性肾脏疾病。妇女还倾向于发展多器官综合征（心脑，心脏 - 凯尼） 经常比男人。多器官功能障碍的性别特异性差异的基础机制仍然存在 理解不佳。先前的工作表明妇女暴露了加速微血管衰老，这是一个过程 以心脏，大脑和肾脏的疾病实施。在这种情况下，系统性炎症已成为 微血管功能障碍和这些慢性疾病状态的发展的主要驱动力。 来自我们小组的初步数据表明，eicosanoids是一个用作生物活性脂质的潜水者 系统性炎症的上游介体可以影响内皮细胞功能，暴露于性二态性 在循环血浆中，与某些血管表型有关。鉴于这些发现，我们假设 局部和全身性类黄花素变异的性二态性均导致微血管的性别差异 功能障碍以及与年龄相关的多器官疾病的性别差异。由我们的早期发现的动机 以及了解与年龄相关疾病的性别差异的决定者和驱动因素的迫切需要 结果，我们建议创建微血管衰老和eicosanoids - Women对全身的评估 衰老的坚韧性（MAE-WEST）专业研究中心卓越的性别差异中心。 利用我们的集体专业知识，我们计划促进对性别特定分子驱动因素的理解 通过3个基础项目，慢性微血管和最终器官疾病。在项目1中，我们将检查 与年龄相关的微血管变化有关的循环类花生酸水平的纵向变化 在两个大型社区人群中的最终器官（心血管，神经认知，肾脏）疾病特征中的功能。在 项目2，我们可能会注册并深入表型，以评估男女 带有器官特异性和全球微血管疾病的类花生酸酯及其反应 对FDA批准的药物（他汀类药物和ACEI/ARB）进行强化医疗疗法的试验。最后，在项目3中 我们将研究性别特异性eicosanoid信号传导对人内皮细胞功能的机理作用以及 在器官特异性疾病以及整个生物体衰老的实验模型中的微血管功能。 该分数不可或缺的一部分，我们将建立一个职业增强中心，该中心将提供强大的培训 以及针对受训者和初级调查人员的精神制。总体而言，这个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，以及 反过来，通过跨学科科学，教育和倡导来实现有效的干预措施。 呢