MAE-WEST SCORE Project 3 Animal

MAE-WEST SCORE 项目 3 动物

基本信息

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
项目类别：
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&apos 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

项目摘要

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，慢性压力源会导致多器官衰老和功能障碍，并最终导致性别仍然是衰老的性质和速度的关键决定因素。在哺乳动物物种中，更明显的是，雌性的寿命与雌性的寿命根本不同。随着人类年龄的增长，女性和男性之间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，也不明确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 和阐明 ADRD、HFpEF 和 CKD 女性占主导地位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。激发了我们的发现以及了解性别差异的决定因素和驱动因素的迫切需要与年龄相关的主要疾病结果，我们建议建立微血管衰老和类二十烷酸 – 女性系统衰老韧性评估（MAE-WEST）（“你永远不会变得更年轻！”）性别差异专业卓越研究中心 (SCORE)，响应 NIH RFA-OD-19-013。我们的目标是形成一个稳健且可持续的学术活动结构，以系统地为中心探讨类二十烷酸、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，最初关注微血管老化对大脑、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合作团队（具有老年病学、心脏病学和肾病学）、流行病学家、基础和转化科学家、分析化学家、我们利用生物统计学家和生物信息学家的集体经验、资源和基础设施。将通过 3 个相互协调且互补的基础项目推进科学事业项目 3 将确定性别特异性类花生酸在受体激活中的因果作用，实验模型和人内皮细胞中的内皮细胞功能障碍和微血管老化该基础科学项目将确定性别特异性类花生酸对内皮细胞的直接因果作用。我们将利用正向遗传学来研究体外细胞激活和实验模型中的微血管功能障碍。确定介导人内皮细胞中性别特异性类花生酸作用的特定受体。