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

肥厚型心肌病(HCM)是最常见的遗传性心脏病 年轻人猝死的最常见原因。虽然基因研究已经 发现了与肥厚性肌病相关的特定肌节基因，他们未能预测哪些 患者会发展成肥厚型心肌炎。这项建议是由越来越多的临床和动物推动的 机械表观遗传因素的模型证据可能解释了这种差异。 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，导致适应性不良的肥大 肥厚性心肌重塑。我们的动机也是需要确定潜在的因素 逆转肥厚型心肌病的药物治疗失败：尽管降血药物 压力可以逆转特发性(非遗传性)肥厚，但它们无法逆转 症状性肉芽肿病的病程。基于这些先前的数据，我们假设HCM 突变改变了诱导肥厚所需的心脏超负荷的大小 重建，并缩短重建可逆的时间框架。 我们的目标是剖析机械载荷通过的分子机制 与肌节突变整合导致结构和功能病理 HCM与肌球蛋白结合蛋白C(MYBPC3)突变有关。这是可能的，因为 第一次因为我们开发了一种中等吞吐量的，人类诱导的 多能干细胞(IPSC)衍生的微型心肌模型系统，允许我们 对IPSC来源的心肌细胞施加受控程度的机械过载。 这一系统将使我们能够表征超负荷对微小心肌的影响 既来自没有疾病突变的IPSC，也来自于经过改造的IPSC HCM患者特异性MYPBC3突变(目标1)。我们将延长我们的磁性水凝胶 微电机机械过载幅度的动态控制技术 原位心肌，使我们能够确定HCM通过 基因突变使心肌细胞对降压药物产生抵抗(AIM 2)。最后，我们将确定机械过载和机械过载之间的分子机制 MYBPC3基因突变与肥厚性重塑(目标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).