Extracellular drivers of myocyte stiffening in diastolic heart disease

舒张性心脏病心肌细胞僵硬的细胞外驱动因素

• 批准号: 10936206
• 负责人: Matthew Caporizzo
• 金额: $ 25.74万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10936206
• 关键词: Adopted; Cardiac; Cardiac Myocytes; Cause of Death; Characteristics; Clinical; Custom; Data; Diastolic heart failure; Extracellular Matrix; FDA approved; Functional disorder; Heart; Heart Diseases; Heart failure; Hypertension; Hypertrophy; Impairment; Measures; Modeling; Molecular; Muscle Cells; Myocardial; Obesity; Organoids; Pathologic; Performance; Preparation; Rattus; Relaxation; Scientist; Signal Transduction; Structure; System; United States National Institutes of Health; Vermont; brain health; cardiovascular health; disability; extracellular; heart function; hypertensive; improved; mechanical properties; stem cells; therapy design

Diastolic heart disease, DHD, is a leading cause of death and disability worldwide. With no FDA approved therapies to improve diastolic dysfunction, the NIH has placed special emphasis on collaborative initiatives between basic scientists and clinicians focusing on understanding the molecular mechanism of diastolic heart failure. Cardiac stiffening is a hallmark of diastolic dysfunction and occurs through mechanisms intrinsic to both cardiomyocytes and extracellular matrix, ECM. With the majority of heart failure therapies designed to target cardiomyocytes and not, the influence of pathologically remodeled ECM on cardiomyocyte and cardiac function is of particular clinical importance. In this proposal we leverage a recently developed cardiac preparation to probe the mechanical properties of the DHD ECM and determine its influence of cardiomyocyte diastolic function. Using an established model of DHD, the obese ZSF1 rat, we determine the degree to which myocardial stiffening depends on cardiomyocyte and ECM stiffening respectively and quantify the structural and compositional changes of ECM in hypertension and DHD. In Aim 2 we determine the influence of DHD ECM on cardiomyocyte structure and function. By maturing cardiac stem cells in decellularized ECM from normal, hypertensive and DHD hearts, we determine the influence of the DHD ECM on cardiomyocyte structure and function. With a custom-adapted mounting system, we will be able to measure diastolic performance of cardiac organoids grown in either normal or DHD ECM. Consistent with our preliminary data, we expect to observe that DHD ECM drives cardiomyocyte hypertrophy, enhanced contractility, and impaired relaxation. These results indicate that the DHD ECM can signal cardiomyocytes to adopt characteristics of diastolic heart disease.

DHD舒张心脏病是全球死亡和残疾的主要原因。未经FDA批准 NIH疗法改善舒张功能障碍，特别强调了协作计划 在基础科学家和临床医生之间，专注于了解舒张压的分子机制 心脏衰竭。心脏僵硬是舒张功能障碍的标志，并通过机制发生 心肌细胞和细胞外基质的固有，ECM。大多数心力衰竭疗法 旨在靶向心肌细胞，而不是靶向心肌细胞的影响 心肌细胞和心脏功能特别重要。在此提案中，我们利用 最近开发了心脏准备，以探测DHD ECM的机械性能并确定 其心肌舒张舒张功能的影响。使用已建立的DHD模型，肥胖的ZSF1大鼠， 我们确定心肌僵硬取决于心肌细胞和ECM僵硬的程度 分别和量化了高血压和DHD中ECM的结构和组成变化。在 AIM 2我们确定DHD ECM对心肌细胞结构和功能的影响。通过成熟 来自正常，高血压和DHD心脏的脱细胞ECM的心脏干细胞，我们确定 DHD ECM对心肌细胞结构和功能的影响。带有定制适应的安装 系统，我们将能够测量以正常或 DHD ECM。与我们的初步数据一致，我们希望观察到DHD ECM驱动器 心肌细胞肥大，收缩力增强和放松受损。这些结果表明 DHD ECM可以发出信号心肌细胞以采用舒张性心脏病的特征。