MAE-WEST SCORE Project 2 Clinical

项目摘要-MAE-WEST评分项目2 在生命过程中，慢性应激源会导致多器官衰老和功能障碍，最终导致 临床疾病的发展。性别仍然是衰老的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，女性的年龄与 男性。随着人类年龄的增加，女性和男性在生物衰老方面的差异 变得更加明显，最终导致女性占主导地位的一些重要病态 疾病状况，包括阿尔茨海默病和相关痴呆症(ADRD)，心力衰竭和 保留射血分数(HFpEF)、进展性慢性肾脏疾病(CKD)，进而导致全身虚弱。 这些重大疾病以女性为主的机制仍不清楚，也不是 可以用性激素的变化或生存偏见来解释。我们的初步工作支持这种性别二型性 在炎症性二十烷类介质中，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的性别差异，包括ADRD、HFpEF和CKD。阐明一个共同之处 ADRD、HFpEF和CKD以女性为主的病理生理学基础是有效的关键 减轻妇女年龄相关疾病过重负担的干预措施。激发了我们的发现和 迫切需要了解重大年龄相关疾病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二十烷类化合物-女性全身性评估 变老的坚韧(Mae-West)(“活到老，活到老！”)专业研究中心 性别差异优秀(得分)，回应NIH RFA-OD-19-013。我们的目标是形成一个强大和 学术活动的可持续结构以系统地询问性别差异为中心 二十烷类化合物、微血管功能障碍和年龄相关的终末器官疾病之间的关系，最初的 重点研究微血管老化对脑、心、肾功能的影响。这一目标将通过一个 出色的临床医生-科学家协作团队(在老年病学、心脏病学和肾脏学方面具有专业知识)， 流行病学家、基础科学家和翻译科学家、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，我们将推动科学事业 通过3个基础项目协调一致、互补但又独立。项目2将决定性别- 二十烷基类化合物与男性和女性微血管生理学的特异性关联及其作用 FDA批准了调节总微血管疾病负担的药物。在一组女性和 临床表型较深的男性，这一临床科学项目将研究性别差异与 二十烷类化合物与主要器官系统(脑、心脏、 肾脏、全身虚弱)，并评估高强度他汀类药物加强化治疗的效果 血管紧张素转换酶抑制剂或血管紧张素转换酶治疗对二十烷类药物和总的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.