MAE-WEST RSC - Eicosanoids Profiling Core

项目摘要-MAE-WEST Score二十碳化合物分析核心 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一个中心假设 炎症性二十烷基类介质的性别二型性导致微血管中的性别差异 功能障碍，进而与年龄相关多器官疾病的性别差异有关，包括ADRD、HFpEF和 CKD。ADRD、HFpEF和CKD女性占优势的共同病理生理学基础 这是有效干预措施的关键，可减轻妇女因年龄引起的疾病的过重负担。我们 建议建立微血管老化和二十烷类化合物--女性对全身衰老韧性的评价 (Mae-West)(“活到老学到老！”)卓越专业研究中心 (分数)性别差异，回应NIH RFA-OD-19-013。我们的目标是形成一个强大和可持续的 学术活动的结构以系统地询问男女关系中的性别差异为中心 在类二十碳化合物、微血管功能障碍和年龄相关的终末器官疾病中，最初的重点是 微血管老化对大脑、心脏和肾脏功能的影响。这一目标将由一位杰出的 临床医生-科学家协作团队(在老年病学、心脏病学和肾脏病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。我们将建立一个专门的 资源支持核心-将被有意创建为独立的二十烷基类分析核心(EPC) 组织内的MAE-WEST得分更大。这种组织功能不仅可以最大限度地利用资源 在整个项目中共享目标，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，及时提供实物服务 实习生试点项目。EPC的专心致志的努力将使有效地生成初步数据 为早期职业生涯和核心活动获得额外和辅助赠款资金，这将进一步 有助于MAE-WEST整体得分的长期可持续性。

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.