MAE-WEST SCORE Project 3 Animal

项目摘要-MAE-WEST评分项目3 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。 激发了我们的发现，并迫切需要了解性别差异的决定因素和驱动因素 与年龄相关的重大疾病预后，我们建议建立微血管老化和二十烷类化合物 --《女性对系统性衰老韧性的评价》(Mae-West)(《活到老，活到老！》) 性别差异专业研究卓越中心(SCORE)，回应NIH RFA-OD-19-013。 我们的目标是形成一个稳健和可持续的学术活动结构，以系统地 探讨二十烷类化合物与微血管功能障碍和年龄相关性的性别差异 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。 这一目标将通过一个出色的临床医生-科学家合作团队(具有老年病学专业知识， 心脏病和肾脏病)、流行病学家、基础科学家和转化学家、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 将通过三个基础项目推进科学事业，这些项目是一致的和互补的 独立自主。项目3将确定性别特异的二十烷类化合物在受体激活中的因果作用， 实验模型和人内皮细胞的内皮细胞功能障碍和微血管老化 细胞。这项基础科学项目将建立性别特异性二十烷醇在内皮细胞上的直接因果作用。 体外细胞激活和实验模型微血管功能障碍。利用前向遗传学，我们将 确定在人类内皮细胞中介导性特定二十烷基类化合物效应的特定受体。

Project Abstract – MAE-WEST SCORE Project 3 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. 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 3 will determine the causal role of sex-specific eicosanoids in receptor activation, endothelial cell dysfunction and microvascular aging in experimental models and human endothelial cells. This basic science project will establish a direct, causal role for sex-specific eicosanoids on endothelial cell activation in vitro and microvascular dysfunction in experimental models. Using forward genetics, we will determine the specific receptors that mediate the effects of sex-specific eicosanoids in human endothelial cells.