Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine

总结 扩张型心肌病（DCM）是心力衰竭和死亡的主要原因。尽管在解开 DCM的遗传基础，缺乏靶向潜在遗传的疾病修饰疗法， 病因学在初步研究中，我们确定了转录因子4（ATF 4）作为一个潜在的治疗靶点， 遗传性DCM的干预措施。ATF 4是介导整合应激反应的关键因子，是一种适应性调节因子。 应激时激活的信号通路。ATF 4是选择性翻译，以响应特定形式的细胞 胁迫诱导参与适应胁迫的基因的表达。在这里，我们提出了一个多学科的 探讨ATF 4介导的一碳代谢调节在心脏中的潜在作用 并为DCM开发新的突变不可知基因疗法。在目标1中，我们将测试ATF 4是否 过表达可以以突变不可知的方式挽救收缩性缺陷，这是DCM的标志， iPSC-CM是为携带不同基因本体中导致DCM突变的患者而衍生的。在目标2中，我们将 研究ATF 4介导的一碳代谢基因表达调控在 心肌细胞功能在目标3中，我们将使用AAV介导的体内ATF 4过表达，并测试是否 ATF 4信号转导可逆转或阻止DCM的体内进展。与传统的基因疗法不同， 这种方法并不能取代有缺陷或缺失的基因。相反，我们的方法旨在触发心脏保护作用， 通过支持心脏中ATF 4依赖的一碳代谢基因表达而产生作用。我们希望 为新的临床相关治疗策略提供概念验证，为突变不可知性铺平道路 治疗遗传性扩张型心肌病这种治疗方法很可能适用于其他类型的心脏病，如心脏病。 失败

Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. Despite the progress in unraveling the genetic basis of DCM, there is a lack of disease-modifying therapies that target the underlying genetic etiology. In preliminary studies, we identified the transcription factor 4 (ATF4) as a potential target for therapeutic interventions in genetic DCM. ATF4 is a critical factor mediating the integrated stress response; an adaptive pathway activated in response to stress. ATF4 is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in adaptation to stress. Here we propose a multidisciplinary approach to explore the potential role of ATF4-mediated regulation of one-carbon metabolism in cardiac physiology and develop novel mutation-agnostic gene therapy for DCM. In Aim 1, we will test whether ATF4 overexpression can rescue the contractility deficit, a hallmark of DCM, in a mutation-agnostic manner using iPSC-CMs derived for patients carrying DCM-causing mutation in diverse gene ontologies. In Aim 2, we will examine the potential role of ATF4-mediated regulation of one-carbon metabolism gene expression in cardiomyocyte function. In Aim 3, we will use AAV-mediated overexpression of ATF4 in vivo and test whether ATF4 signaling could reverse or halt the progression of DCM in vivo. Unlike conventional gene therapies, our approach does not replace a faulty or missing gene. Instead, our approach aims at triggering a cardioprotective effect by bolstering the ATF4-dependent one-carbon metabolism gene expression in the heart. We hope to provide proof-of-concept for a new clinically relevant therapeutic strategy, paving the way for mutation-agnostic treatments for genetic DCM. Such treatments are likely to apply to other types of cardiac diseases such as heart failure.