Uncovering The Mechanogenomic Basis For Cardiac Plasticity

项目摘要 心脏病在这个国家80多年来一直是导致死亡的主要原因。两个基本 心力衰竭的驱动因素是结构重塑和基质沉积（纤维化）。两者都缺乏针对性 预防或逆转的干预措施强调需要破译其分子基础， 适应不良的结构重塑机械力影响全身的细胞结构， 尤其是在血管、肌肉和骨骼中。根据这些发现，我们最近证明， 肌细胞生物力学是心脏结构重塑的性质和严重性的主要驱动力。这些 这些数据导致了对心肌细胞机械状态的计算描述的发展，称为 紧张指数，它胜过所有其他分子遗传指标，作为心脏结构的预测指标。 小鼠和遗传性心肌病患者的表型和疾病状态。这种新的机械模式 为早期预防和定制机械干预提供了希望， 生长和几何形状恢复正常，前提是解决以下关键问题：（1） 调节机械稳态反馈机制的成纤维细胞和肌细胞的集体作用 指导心脏可塑性;（2）机械不平衡如何与心脏重塑相关 成纤维细胞和肌细胞感知;（3）机械失衡如何改变肌细胞表观遗传和 转录模式使用一种新的工程小鼠遗传学方法，允许战术调整， 心脏的机械性能，这个应用程序将通过测试中央 假设机械不平衡的大小和方向引发可预测的建筑 通过平衡细胞内和细胞外力学而可逆的重塑。这种方法克服了 领域无法研究体内的机械关系，这将首次揭示如何协调 机械源的作用和整合指导心脏的可塑性。在这里，这些机械的自我平衡 反馈机制将被用来发现心脏机械状态的生物标志物， 结构重塑我们预计这些发现将满足临床上未满足的预测性需求。 心脏适应不良纤维化和结构重塑的诊断工具和预防策略。

PROJECT SUMMARY Heart disease has been the leading cause of death in this country for over eighty years. Two fundamental drivers of heart failure are architectural remodeling and matrix deposition (fibrosis). Both of which lack targeted interventions for their prevention or reversal underscoring the need to decipher the molecular basis for this maladaptive structural remodeling. Mechanical forces influence cellular architecture throughout the body, especially in blood vessels, muscle and bone. In accordance with these findings we recently demonstrated that myocyte biomechanics is a primary driver of the nature and severity of cardiac structural remodeling. These data led to the development of a computational description of a cardiac myocyte's mechanical state called the tension index, which trumped all other molecular-genetic metrics as a predictor of the heart's architectural phenotype and disease state in mice and inherited cardiomyopathy patients. This new mechanical paradigm holds promise for early prevention and customized mechanical interventions that could reprogram maladaptive growth and geometry back to normal provided the following key questions are resolved: (1) How do the collective actions of fibroblasts and myocytes that regulate mechanical homeostatic feedback mechanisms guide cardiac plasticity; (2) How is mechanical disequilibrium that is associated with cardiac remodeling sensed by fibroblasts and myocytes; and (3) how do mechanical imbalances alter myocyte epigenetic and transcriptional patterns. Using a newly engineered mouse genetics approach that permits the tactical tuning of the heart's mechanical properties, this application will address these questions by testing the central hypothesis that the magnitude and direction of mechanical disequilibrium initiates predictable architectural remodeling that is reversible by balancing intra and extracellular mechanics. This approach overcomes the field's inability to study mechanical relationships in vivo, which will reveal for the first time how coordinated actions and integration of mechanical sources directs cardiac plasticity. Here these mechanical homeostatic feedback mechanisms will be coopted to discover biomarkers of the heart's mechanical state and hence structural remodeling. We anticipate these findings will fulfill the clinically unmet need for a predictive diagnostic tool and preventive strategy for maladaptive fibrotic and architectural remodeling of the heart.