Biomaterial Platforms to Model the Role of Mechanical Overload in MYBPC3-Linked Hypertrophic Cardiomyopathy

肥厚性心肌病（HCM）是最常见的遗传性心脏病， 是年轻人猝死的最常见原因虽然遗传学研究 确定了与HCM相关的特定肌节基因，他们未能预测 患者会出现HCM。该提案的动机是通过增加临床和动物 机械表观遗传因素的模型证据可能解释这种差异。 这些数据表明，由高血压引起的心脏机械负荷过重， 可与肌节突变共同作用， HCM的重塑我们的动机还在于需要查明造成这种情况的因素， 药物治疗逆转HCM的失败：尽管减少血液循环的药物 压力可以逆转特发性（非遗传性）肥大，他们未能逆转 症状性HCM的病程。基于这些先前的数据，我们假设HCM 突变改变了诱导肥厚性心肌病所需的心脏超负荷的程度， 重塑并缩短重塑可逆的时间框架。 我们的目标是剖析分子机制，通过机械加载 与肌节突变整合，导致结构和功能病理学， HCM与肌球蛋白结合蛋白C（MYBPC3）突变有关。都有可能出现这种情况 第一次是因为我们已经开发了一种中等通量的，人类诱导的 多能干细胞（iPSC）衍生的微型心肌模型系统，使我们能够 对iPSC衍生的心肌细胞施加受控大小的机械过载。 该系统将使我们能够表征超负荷对微型心肌的影响 来源于没有疾病突变的iPSC和工程化的iPSC HCM患者特异性MYPBC3突变（目的1）。我们将把磁性水凝胶 动态控制微机械过载大小的技术， 心肌原位，使我们能够确定HCM的机制， 突变使心肌细胞对降压疗法产生抵抗（Aim 2）。最后，我们将确定连接机械过载和 MYBPC3突变伴肥厚性重塑（Aim 3）。

Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart disease and the most common cause of sudden death in young people. While genetic studies have identified specific sarcomere genes associated with HCM, they fail to predict which patients will develop HCM. This proposal is motivated by mounting clinical and animal model evidence for mechanical epigenetic factors possibly explaining this variance. These data suggest that mechanical overload on the heart, caused by hypertension, can act together with sarcomere mutations to cause maladaptive hypertrophic remodeling in HCM. We are also motivated by the need to identify the factors underlying the failure of drug treatments to reverse HCM: although medicines that reduce blood pressure can reverse idiopathic (non-genetic) hypertrophy, they fail to reverse the course of symptomatic HCM. Based upon these prior data, we hypothesize that HCM mutations alter the magnitude of cardiac overload required to induce hypertrophic remodeling and shorten the timeframe over which remodeling is reversible. We aim to dissect the molecular mechanisms through which mechanical loading integrates with sarcomere mutations to cause structural and functional pathology in HCM linked to mutations in Myosin Binding Protein C (MYBPC3). This is possible for the first time because we have developed a medium-throughput, human induced pluripotent stem cell (iPSC) derived micro-heart muscle model system that allows us to apply a controlled magnitude of mechanical overload to iPSC-derived cardiomyocytes. This system will enable us to characterize the effects of overload on micro-heart muscle derived from both iPSC without disease mutations, and from iPSC engineered to harbor HCM patient specific MYPBC3 mutations (Aim 1). We will extend our magnetic hydrogel technologies to dynamically control the magnitude of mechanical overload on micro- heart muscles in situ, enabling us to determine mechanisms through which HCM mutations render cardiomyocytes resistant to blood pressure reducing therapeutics (Aim 2). Finally, we will determine molecular mechanisms linking mechanical overload and MYBPC3 mutations with hypertrophic remodeling (Aim 3).