MAE-WEST SCORE Project 2 Clinical

项目摘要- MAE-WEST SCORE项目2 在生命过程中，慢性应激源导致多器官衰老和功能障碍，最终， 临床疾病的发展。性仍然是衰老的性质和速度的关键决定因素， 中心blog在哺乳动物物种中，更明显的是，雌性的衰老与雌性的衰老根本不同。 男性。随着人类生理年龄的增长，女性和男性之间的生物衰老差异 变得更加明显，最终在女性占主导地位的一些重要的病态 疾病状况，尤其包括阿尔茨海默病和相关痴呆（ADRD）、心力衰竭伴 射血分数保留（HFpEF）、进行性慢性肾病（CKD），进而全身虚弱。 这些主要发病率女性占优势的机制仍然未知， 这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两性异形 在炎症性类花生酸介质中，微血管功能障碍的性别差异，反过来， 年龄相关多器官疾病的性别差异，包括ADRD、HFpEF和CKD。阐明一个共同的 ADRD、HFpEF和CKD女性优势的病理生理基础是有效治疗的关键。 采取干预措施，减轻妇女与年龄有关的疾病的过度负担。激发了我们的发现， 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花生酸-妇女的评价系统 1997年，梅-韦斯特（MAE-WEST）在《变年轻永远不嫌老》（You are never too old to become younger！专业研究中心 根据NIH RFA-OD-19-013，对性别差异进行卓越评分。我们的目标是建立一个强大的， 学术活动的可持续结构，集中在系统地询问性别差异， 类花生酸、微血管功能障碍和年龄相关终末器官疾病之间的关系， 专注于微血管老化对大脑、心脏和肾脏功能的影响。这一目标将通过 杰出的临床医生-科学家合作团队（具有老年病学，心脏病学和肾脏病学的专业知识）， 流行病学家、基础和转化科学家、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个基础项目协调一致，互补但独立。项目2将决定性别- 类二十烷酸与女性和男性微血管生理学的特异性关联以及 FDA批准的调节总微血管疾病负担的药物。在一组女性样本中， 男性与深临床表型，这个临床科学项目将研究性别差异的关系， 类二十烷酸与主要器官系统（脑，心脏， 肾脏、全身虚弱），并评估高强度他汀类药物加 ACEi或ARB治疗对类花生酸特征和总微血管疾病负荷的影响。

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.