Probing sex differences in myocardial fibrosis at multiple length scales using biomaterials

使用生物材料在多个长度尺度上探讨心肌纤维化的性别差异

• 批准号: 10687446
• 负责人: Brian Alberto Aguado
• 金额: $ 142.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687446
• 关键词: Award; Biocompatible Materials; Biological; Biology; Biomedical Engineering; Cardiac; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Research; Dependence; Development; Disease Progression; Disease model; EFRAC; Equity; Extracellular Matrix; Female; Fibroblasts; Functional disorder; Gender; Heart; Heart failure; Hypertension; Individual; Inflammation; Injury; Laboratories; Left; Length; Medicine; Mission; Modeling; Myocardial Infarction; Myocarditis; Myofibroblast; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physiologic intraventricular pressure; Public Health; Research; Sex Differences; Signal Transduction; Symptoms; Technology; Tissues; Treatment Protocols; Treatment outcome; United States; United States National Institutes of Health; X Chromosome; biological sex; clinical practice; coronary fibrosis; dosage; experience; health disparity; inherited cardiomyopathy; innovation; male; myocardial injury; preservation; programs; sex; standard of care; therapeutically effective; treatment disparity

PROJECT SUMMARY My proposed research for the NIH Director’s New Innovator Award seeks to determine how biological sex modulates myocardial fibrosis and develop innovative models of sex-specific tissue remodeling using advanced biomaterial technologies. Myocardial fibrosis, or the aberrant remodeling of extracellular matrix in the heart, is a common outcome of several cardiac pathologies, including ventricular pressure overload, myocardial infarct, hypertension, cardiac inflammation, and/or genetic cardiomyopathies, all of which can lead to heart failure. Even though standard-of-care medications have been useful to help relieve heart failure symptoms, clinically effective therapeutics to halt and reverse myocardial fibrosis progression are not available. Biological sex is a potent modulator of myocardial fibrosis. For example, clinical studies have established that patients experiencing diastolic dysfunction and develop heart failure with preserved ejection fraction (HFpEF) are 2.84-fold more likely to be female. Unfortunately, the historical dependence on male-biased disease models for understanding myocardial fibrosis has left a significant gap in understanding female-specific heart failure mechanisms, causing significant health disparities in treatment outcomes for female patients. To change course, our laboratory will develop sex-specific cardiac fibrosis models and determine paths toward sex-specific therapies to halt disease progression and move toward equitable treatment outcomes. My proposal outlines an innovative research program to identify how X-chromosome dosage in cardiac myofibroblasts gives rise to sex differences in myocardial fibrosis after injury. Our three project thrusts centralize around the hypothesis that X-chromosome dosage regulates (1) myofibroblast activation signaling networks in cardiac fibroblasts, (2) extracellular matrix remodeling after myocardial injury, and (3) inflammation during myocardial fibrosis in females. Understanding sex-specific mechanisms of myocardial fibrosis may inform paths toward sex-specific treatment protocols and significantly impact clinical practice. If successful, the proposed research will significantly and broadly advance our fundamental understanding of sex-specific biology in myocardial fibrosis and other cardiovascular diseases.

项目摘要 我针对NIH董事的新创新者奖提议的研究旨在确定生物学 性别调节心肌纤维化并开发性别特异性组织重塑的创新模型 使用先进的生物材料技术。心肌纤维化或细胞外的异常重塑 心脏中的基质是多种心脏病理的共同结果，包括心室压力超负荷， 心肌基础设施，高血压，心脏感染和/或遗传性心肌病，所有这些都可以领导 心力衰竭。即使护理标准药物对挽救心力衰竭有用 症状，临床上有效的治疗，以停止和逆转心肌纤维化进展。 生物性别是心肌纤维化的潜在调节剂。例如，临床研究确定 患有舒张功能障碍并通过保留的射血分数（HFPEF）出现心力衰竭的患者（HFPEF） 女性的可能性更高2.84倍。不幸的是，对男性偏见模型的历史依赖 为了理解心肌纤维化，在理解女性特异性心力衰竭方面留下了很大的差距 机制，导致女性患者的治疗结果严重健康差异。改变 当然，我们的实验室将开发性别特异性心脏纤维化模型，并确定通往 性别特定的疗法，以阻止疾病进展并朝着公平的治疗结果发展。我的 提案概述了一项创新的研究计划，以确定X染色体剂量如何心脏剂量 肌纤维细胞受伤后会导致心肌纤维化的性别差异。我们的三个项目集中 围绕X染色体剂量调节的假设（1）肌纤维细胞激活信号网络 心脏成纤维细胞，（2）心肌损伤后细胞外基质重塑，（3）在 女性心肌纤维化。了解心肌纤维化的性别特异性机制可能会导致路径 采用特定性别治疗方案，并显着影响临床实践。如果成功，提议 研究将显着，广泛地提高我们对性别特定生物学的基本理解 心肌纤维化和其他心血管疾病。