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: 10817498
• 负责人: Cathleen Noel Bairey Merz
• 金额: $ 16.47万
• 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/10817498
• 关键词: Acceleration; 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; 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; Science; Scientific Advances and Accomplishments; Scientist; Secure; Sex Differences; Signal Transduction; Specialized Center; Structure; Syndrome; System; Therapeutic; Training; Variant; Whole Organism; Woman; Women' s Health; Work; age effect; age related; 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; 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 总体评分 在整个生命周期中，女性的年龄与男性不同，最终导致女性在慢性病中占主导地位 射血分数保留的心力衰竭、阿尔茨海默病和相关痴呆等疾病，以及 慢性肾脏疾病。女性也更容易出现多器官综合征（心脑、心肾） 比男性更频繁。多器官功能障碍中性别特异性差异的机制仍然存在 不太了解。先前的研究表明，女性表现出加速的微血管老化，这是一个过程 与心脏、大脑和肾脏疾病有关。在此背景下，全身性炎症已成为一种 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化的生物活性脂质，可作为 全身炎症的上游介质，可以影响内皮细胞功能，表现出性别二态性 存在于循环血浆中，并且与某些血管表型相关。鉴于这些发现，我们假设 局部和全身类二十烷酸变异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。受到我们早期发现的启发 以及了解年龄相关疾病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类二十烷酸 – 女性全身评估 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，我们计划增进对性别特异性分子驱动因素的理解 通过 3 个基础项目研究慢性微血管和终末器官疾病。在项目 1 中，我们将检查 循环类二十烷酸水平的纵向变化与年龄相关的微血管变化有关 两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表型分析，以评估这种关系 类二十烷酸对器官特异性以及整体微血管疾病负担的影响及其反应 尝试使用 FDA 批准的药物（他汀类药物和 ACEi/ARB）进行强化药物治疗。最后，在项目3中， 我们将研究性别特异性类二十烷酸信号传导对人内皮细胞功能的机制作用以及 器官特异性疾病以及整个有机体衰老的实验模型中的微血管功能。作为 作为该 SCORE 的组成部分，我们将建立一个职业提升中心，提供强有力的培训 以及对实习生和初级研究者的指导。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性别差异的理解， 反过来，通过跨学科的科学、教育和宣传来实现有效的干预。 ！

项目成果

INOCA and MINOCA: Are Women's Heart Centres the Answer to Understanding and Management of These Increasing Populations of Women (and Men)?

INOCA 和 MINOCA：女性心脏中心是理解和管理这些不断增加的女性（和男性）人口的答案吗？

• DOI: 10.1016/j.cjca.2022.06.016
• 发表时间: 2022
• 期刊: The Canadian journal of cardiology
• 作者: Pacheco,Christine;Luu,Judy;Mehta,PujaK;Wei,Janet;Gulati,Martha;BaireyMerz,CNoel
• 通讯作者: BaireyMerz,CNoel

Premature menopause and cardiovascular disease: can we blame estrogen?

过早绝经和心血管疾病：我们可以归咎于雌激素吗？

• DOI: 10.1093/eurheartj/ehac321
• 发表时间: 2022
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Torbati,Tina;Shufelt,Chrisandra;Wei,Janet;NoelBaireyMerz,C
• 通讯作者: NoelBaireyMerz,C

Apolipoproteins Quantified Using Blood Volumetric Absorptive Microsampling and High-Throughput Mass Spectrometry for Risk Assessment in Ischemic Heart Disease.

使用血液容量吸收微量采样和高通量质谱定量载脂蛋白，用于缺血性心脏病的风险评估。

• DOI: 10.1161/circulationaha.123.066034
• 发表时间: 2024
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Marano,Paul;Mouapi,Kelly;Kim,Andy;Mastali,Mitra;vandenBroek,Irene;Manalo,Danica;Fu,Qin;Cheng,Susan;Shufelt,Chrisandra;Spiegel,Brennan;BaireyMerz,CNoel;VanEyk,JenniferE
• 通讯作者: VanEyk,JenniferE

A genome-wide association study identifies 41 loci associated with eicosanoid levels.

• DOI: 10.1038/s42003-023-05159-5
• 发表时间: 2023-07-31
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Rhee, Eugene P.;Surapaneni, Aditya L.;Schlosser, Pascal;Alotaibi, Mona;Yang, Yueh-ning;Coresh, Josef;Jain, Mohit;Cheng, Susan;Yu, Bing;Grams, Morgan E.
• 通讯作者: Grams, Morgan E.

Cardiac microstructural alterations measured by echocardiography identify sex-specific risk for heart failure.

• DOI: 10.1136/heartjnl-2022-320876
• 发表时间: 2022-10-28
• 期刊: HEART
• 影响因子: 5.7
• 作者: Kwan, Alan;Demosthenes, Emmanuella;Salto, Gerran;Ouyang, David;Nguyen, Trevor;Nwabuo, Chike C.;Luong, Eric;Hoang, Amy;Osypiuk, Ewa;Stantchev, Plamen;Kim, Elizabeth H.;Hiremath, Pranoti;Li, Debiao;Vasan, Ramachandran;Xanthakis, Vanessa;Cheng, Susan
• 通讯作者: Cheng, Susan