MAE-WEST SCORE Project 2 Clinical

MAE-WEST SCORE 项目 2 临床

• 批准号: 10450762
• 负责人: Cathleen Noel Bairey Merz
• 金额: $ 72.85万
• 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/10450762
• 关键词: Address; Age; Aging; Alzheimer' s disease related dementia; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Biological Aging; Biology; Blood Vessels; Brain; Cardiology; Cell physiology; Centers of Research Excellence; Chronic; Chronic Kidney Failure; Chronology; Clinical; Clinical Sciences; Clinical Trials; Cognitive; Coronary; Data; Development; Diagnostic tests; Disease; Disease Outcome; Disease Progression; EFRAC; Eicosanoids; Elderly; Endothelial Cells; Endothelium; Enrollment; Epidemiologist; Evaluation; FDA approved; Failure; Female; Foundations; Functional disorder; Funding; Geriatrics; Goals; Gonadal Steroid Hormones; Heart; Heart failure; Human; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Intervention Trial; Investigation; Ischemia; Kidney; Lead; Life Cycle Stages; Longevity; Measures; Mediator of activation protein; Medical; Men' s Role; Microvascular Dysfunction; Molecular; Morbidity - disease rate; National Institute on Aging; Nature; Nephrology; Organ; Peripheral; Phenotype; Physiological; Physiology; Plasma; Play; Population Analysis; Process; Prospective Studies; Public Health; Randomized; Renal function; Request for Applications; Research; Resources; Role; Sampling; Scientific Advances and Accomplishments; Scientist; Severities; Sex Differences; Specialized Center; Stress; Structure; Testing; Urine; Variant; Woman; Women' s Role; Work; age effect; age related; base; body system; burden of illness; cardiac magnetic resonance imaging; clinical development; clinical phenotype; effective intervention; endothelial dysfunction; experience; frailty; functional status; heart function; improved; intervention effect; kidney dysfunction; male; men; microvascular aging; population based; preservation; prevent; prospective; response; retinal imaging; sex; sexual dimorphism; stressor; systemic inflammatory response; targeted treatment; tonometry; trait; translational scientist; treatment as usual; treatment strategy

Project Abstract – MAE-WEST SCORE Project 2 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 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 2 will determine the sex- specific association of eicosanoids with microvascular physiology in women and men and the role of FDA approved agents in modulation of total microvascular disease burden. In a sample of women and men with deep clinical phenotyping, this clinical science project will examine sex differences in the relations of eicosanoids with the co-occurrence of microvascular aging traits across major organ systems (brain, heart, kidney, systemic frailty) and evaluate the effects of intensive medical treatment with high-intensity statin plus ACEi or ARB therapy on both eicosanoid profiles and total microvascular disease burden.

项目摘要 - MAE-West分数项目2 在生活过程中，长期压力源导致多器官衰老和功能障碍，最终导致 临床疾病的发展。性仍然是对衰老的性质和节奏的关键决定者 长寿。在哺乳动物的物种中，更清楚的是，女性的年龄与 男性。随着人类年龄的增长，男女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许多重要病态 疾病状况，包括尤其是阿尔茨海默氏病和相关痴呆症（ADRD），心力衰竭 保留的射血分数（HFPEF），进行性慢性肾脏疾病（CKD）和全身脆弱。 女性占主导地位的机制尚不清楚，不是 用性激素或生存偏见的变化解释。我们的初步工作支持性二态性 在炎症性类类媒体中，介体有助于微血管功能障碍的性别差异，而对 与年龄相关的多器官疾病的性别差异，包括ADRD，HFPEF和CKD。阐明一个共同点 ADRD，HFPEF和CKD的女性优势的病理生理基础是有效的关键 减少女性年龄相关疾病过量烧伤的干预措施。激发了我们的发现和 了解主要年龄相关疾病中性别差异的决定者和驱动因素的批判性需求 结果，我们建议建立微血管衰老和类花生素 - 妇女对系统的评估 衰老的坚韧性（Mae-West）（“您永远不会太老，无法年轻！”）专业研究中心 对NIH RFA-OD-19-013的卓越性别差异（得分）。我们的目标是形成强大的 学术活动的可持续结构以系统地询问性别差异的中心 类花生酸，微血管功能障碍和与年龄相关的末期疾病之间的关系，初始 专注于微血管衰老对大脑，心脏和肾功能的影响。这个目标将通过一个 临床科学家的杰出合作团队（具有老年医学，心脏病学和肾脏学专业知识）， 流行病学家，基础和翻译的科学家，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，我们将推进科学企业 通过3个基础项目结盟和互补但独立。项目2将确定性别 - eicosanoids与男性和男性的微血管生理学的特定关联以及 FDA批准的药物调节总微血管疾病负担。在女性样本中 具有深度临床表型的男性，该临床科学项目将检查与 eicosanoids与主要器官系统（大脑，心脏， 肾脏，全身脆弱），并评估高强度汀类药物的强化医疗治疗的影响 eicosanoid谱和总微血管疾病伯恩的ACEI或ARB治疗。