MAE-WEST RSC - Eicosanoids Profiling Core

项目摘要 – MAE-WEST SCORE 类二十烷酸分析核心 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一个中心假设： 炎症类二十烷酸介质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，包括 ADRD、HFpEF 和 慢性肾病。阐明 ADRD、HFpEF 和 CKD 女性占多数的共同病理生理学基础 是采取有效干预措施减少妇女因年龄相关疾病而过度负担的关键。我们 提议建立微血管衰老与类二十烷酸——女性全身衰老韧性评估 (MAE-WEST)（“你永远不会太老而变得年轻！”）卓越研究专业中心 (SCORE) 关于性别差异，回应 NIH RFA-OD-19-013。我们的目标是建立一个强大且可持续的 以系统地探讨关系中的性别差异为中心的学术活动结构 类二十烷酸、微血管功能障碍和与年龄相关的终末器官疾病，最初的重点是 微血管老化对大脑、心脏和肾脏功能的影响。这一目标将由杰出的 临床医生-科学家协作团队（具有老年病学、心脏病学和肾病学专业知识）， 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。我们将设立专门的 资源支持核心 - 类二十烷酸分析核心 (EPC)，将特意创建为独立的 更大的 MAE-WEST SCORE 中的组织。这种组织功能不仅可以最大限度地利用资源 跨项目目标共享，但也确保能够单独和独立地增强 对早期职业调查员进行方法培训，重要的是，及时向他们提供实物服务 实习生试点项目。 EPC 的不懈努力将有助于有效生成初步数据 为早期职业和核心活动获取额外和辅助赠款资金，这将另外 为整个 MAE-WEST SCORE 的长期可持续性做出贡献。

Project Abstract – MAE-WEST SCORE Eicosanoids Profiling Core 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 a central hypothesis 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. 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. We will establish a dedicated Resource Support Core - an Eicosanoids Profiling Core (EPC) that will be intentionally created as standalone organization within the larger MAE-WEST SCORE. This organizational feature will not only maximize resource sharing across the project aims but also ensure the ability to separately and independently augment the methodological training of early career investigators and, importantly, timely provision of in-kind services for trainee pilot projects. The dedicated effort of the EPC will allow efficient generation of preliminary data for acquiring additional and ancillary grant funding for both early career and core activities, which will additionally contribute to the long-term sustainability of the MAE-WEST SCORE as a whole.