MAE-WEST SCORE Project 3 Animal

MAE-WEST SCORE 项目 3 动物

• 批准号: 10198762
• 负责人: John YJ Shyy
• 金额: $ 81.9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10198762
• 关键词: Accounting; Adult; Age; Aging; Alzheimer' s disease related dementia; Animals; Anti-Inflammatory Agents; Aspirin; Attenuated; Basic Science; Binding; Bioinformatics; Biological Aging; Biometry; Blood Circulation; Blood Vessels; Brain; CRISPR/Cas technology; Cardiology; Cell physiology; Cell surface; Cells; Centers of Research Excellence; Chronic; Chronic Kidney Failure; Chronology; Complex; Development; Disease; Disease Outcome; EFRAC; Eicosanoids; Elderly; Endothelial Cells; Enzymes; Epidemiologist; Epigenetic Process; Etiology; Evaluation; Experimental Models; Failure; Family; Female; Foundations; Functional disorder; G-Protein-Coupled Receptors; Gene Expression; Genetic Transcription; Geriatrics; Goals; Gonadal Steroid Hormones; Health; Heart; Heart Diseases; Heart failure; Hormonal; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Intravenous; Kidney; Kidney Diseases; Laboratories; Life Cycle Stages; Link; Lipids; Longevity; Mediating; Mediator of activation protein; Microvascular Dysfunction; Morbidity - disease rate; Mus; Nature; Nephrology; Neurodegenerative Disorders; Non-Steroidal Anti-Inflammatory Agents; Nuclear Receptors; Organ; Pathway interactions; Phenotype; Polyunsaturated Fatty Acids; Process; Prostaglandin-Endoperoxide Synthase; Public Health; RNA Interference; Receptor Activation; Receptor Signaling; Regulation; Renal function; Request for Applications; Resources; Role; Scientific Advances and Accomplishments; Scientist; Serum; Sex Differences; Signal Transduction; Specialized Center; Structure; System; Variant; Vasodilation; Woman; Work; age difference; age effect; age related; base; biological sex; body system; brain endothelial cell; burden of illness; clinical development; disease disparity; effective intervention; endothelial dysfunction; experience; experimental study; exposed human population; forward genetics; frailty; heart function; improved; in vivo; male; men; microvascular aging; preservation; receptor; response; senescence; sex; sex disparity; sexual dimorphism; stressor; systemic inflammatory response; therapeutic development; translational scientist

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.

项目摘要- MAE-WEST SCORE项目3 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一个中心假设， 炎症性类花生酸介质的性别二型性导致微血管 功能障碍，反过来，与年龄相关的多器官疾病的性别差异，包括ADRD，HFpEF和 慢性肾脏病。阐明ADRD、HFpEF和CKD女性优势的共同病理生理学基础 是采取有效干预措施减少妇女年龄相关疾病过度负担的关键。 激发了我们的研究结果，并迫切需要了解性别差异的决定因素和驱动因素， 主要年龄相关疾病的结果，我们建议建立微血管老化和类花生酸 - 女性系统老化韧性评估（MAE-WEST）（“你永远不会太老，变得年轻！”） 性别差异卓越研究专业中心（SCORE），响应NIH RFA-OD-19-013。 我们的目标是形成一个强大的和可持续的学术活动结构， 询问类二十烷酸、微血管功能障碍和年龄相关性之间关系的性别差异 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。 这一目标将由一个杰出的临床医生-科学家（具有老年医学专业知识， 心脏病学和肾脏病学），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， 将通过3个基础项目来推进科学事业，这些项目是一致和互补的， 独立的项目3将确定性别特异性类花生酸在受体激活中的因果作用， 内皮细胞功能障碍和微血管老化的实验模型和人内皮细胞 细胞这个基础科学项目将建立一个直接的，因果关系的作用，性别特异性类花生酸对内皮细胞 体外细胞活化和实验模型中的微血管功能障碍。利用正向遗传学， 确定介导人类内皮细胞中性别特异性类花生酸效应的特异性受体。