MAE-WEST SCORE Project 2 Clinical

项目摘要 – MAE-WEST SCORE 项目 2 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。性别仍然是衰老性质和速度的关键决定因素，并最终 长寿。在哺乳动物物种中，更明显的是，雌性的年龄与雄性不同。 男性。随着人类实际年龄的增长，女性和男性的生物衰老存在差异 变得更加明显，最终导致许多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 可以用性激素的变化或生存偏差来解释。我们的初步工作支持性别二态性 炎症类二十烷酸介质会导致微血管功能障碍的性别差异，进而导致 年龄相关多器官疾病（包括 ADRD、HFpEF 和 CKD）的性别差异。阐明一个共同点 ADRD、HFpEF 和 CKD 女性占主导地位的病理生理学基础是有效治疗的关键 减少妇女因年龄相关疾病造成的额外负担的干预措施。激发了我们的发现和 迫切需要了解主要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二十烷酸——女性全身系统评估 老化韧性（MAE-WEST）（“你永远不会变得更年轻！”）专业研究中心 性别差异卓越奖 (SCORE)，回应 NIH RFA-OD-19-013。我们的目标是建立一个强大而 学术活动的可持续结构以系统地探讨性别差异为中心 类二十烷酸、微血管功能障碍和年龄相关的终末器官疾病之间的关系，最初 重点关注微血管老化对大脑、心脏和肾脏功能的影响。这一目标将通过 杰出的临床医生-科学家协作团队（拥有老年病学、心脏病学和肾脏病学方面的专业知识）， 流行病学家、基础科学家和转化科学家、分析化学家、生物统计学家和生物信息学家。 利用我们的集体经验、资源和基础设施，我们将推进科学事业 通过 3 个基础项目，这些项目相互协调、互补但独立。项目 2 将确定性别- 类二十烷酸与女性和男性微血管生理学的特定关联及其作用 FDA 批准了调节总体微血管疾病负担的药物。在女性样本中 具有深入临床表型的男性，这个临床科学项目将检查以下关系中的性别差异 类二十烷酸与主要器官系统（脑、心脏、 肾、全身虚弱）并评估高强度他汀类药物联合强化治疗的效果 ACEi 或 ARB 治疗对类二十烷酸谱和总微血管疾病负担的影响。

Project Abstract – MAE-WEST SCORE Project 2 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 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 2 will determine the sex- specific association of eicosanoids with microvascular physiology in women and men and the role of FDA approved agents in modulation of total microvascular disease burden. In a sample of women and men with deep clinical phenotyping, this clinical science project will examine sex differences in the relations of eicosanoids with the co-occurrence of microvascular aging traits across major organ systems (brain, heart, kidney, systemic frailty) and evaluate the effects of intensive medical treatment with high-intensity statin plus ACEi or ARB therapy on both eicosanoid profiles and total microvascular disease burden.