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。虽然遗传学研究已 确定了与 HCM 相关的特定肌节基因，但他们未能预测哪些基因 患者将发展为 HCM。该提案的动机是不断增加的临床和动物 可能解释这种差异的机械表观遗传因素的模型证据。 这些数据表明，由高血压引起的心脏机械超负荷， 可以与肌节突变一起作用，导致适应不良肥大 HCM 重塑。我们还受到确定潜在因素的需要的激励 药物治疗未能逆转肥厚性心肌病：尽管药物可以减少血液 压力可以逆转特发性（非遗传性）肥大，但无法逆转 有症状的 HCM 病程。根据这些先前的数据，我们假设 HCM 突变改变了诱导肥厚所需的心脏超负荷程度 改造并缩短改造可逆的时间范围。 我们的目标是剖析机械加载的分子机制 与肌节突变整合，引起结构和功能病理学 HCM 与肌球蛋白结合蛋白 C (MYBPC3) 的突变有关。这对于 第一次是因为我们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机械过载幅度。 该系统将使我们能够表征超负荷对微心肌的影响 源自无疾病突变的 iPSC 和经过改造的 iPSC HCM 患者特异性 MYPBC3 突变（目标 1）。我们将扩展我们的磁性水凝胶 动态控制微机械过载幅度的技术 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治疗产生耐药性（目的 2）。最后，我们将确定将机械过载与机械过载联系起来的分子机制。 MYBPC3 突变伴有肥大性重塑（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).