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 我为NIH主任的新创新者奖提出的研究旨在确定生物学如何 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基质的异常重塑 心脏中的基质是几种心脏病的常见结果，包括心室压力超负荷， 心肌梗塞、高血压、心脏炎症和/或遗传性心肌病，所有这些都可能导致 心脏衰竭尽管标准治疗药物有助于缓解心力衰竭， 由于心肌纤维化的症状，阻止和逆转心肌纤维化进展的临床有效疗法不可用。 生物性别是心肌纤维化的一个有效调节因子。例如，临床研究已经确定， 发生舒张功能障碍并发生射血分数保留心力衰竭（HFpEF）的患者 是女性的可能性高出2.84倍。不幸的是，历史上对男性偏见的疾病模型的依赖 对于理解心肌纤维化，在理解女性特异性心力衰竭方面存在重大差距， 机制，导致女性患者在治疗结果方面存在显著的健康差异。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，并确定实现 性别特异性治疗，以阻止疾病进展，并走向公平的治疗结果。我 提案概述了一项创新的研究计划，以确定X染色体剂量如何在心脏 肌成纤维细胞引起损伤后心肌纤维化的性别差异。我们的三个项目重点是 围绕X染色体剂量调节（1）肌成纤维细胞激活信号网络的假设， 心肌成纤维细胞，（2）心肌损伤后细胞外基质重塑，和（3） 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告知路径 性别特异性治疗方案，并显着影响临床实践。如果成功，建议 研究将显著和广泛地推进我们对性别特异性生物学的基本理解， 心肌纤维化和其他心血管疾病。