iPSC-CM Modeling to Define Sodium-Calcium Dysfunction in Heart Failure

项目摘要 随着新疗法的停滞不前，心力衰竭(HF)仍然是一个主要的临床和经济负担。 在过去的二十年里。改进疗法的一个重要障碍是对 钠/钙失衡在心力衰竭中的作用及其在电和机械功能障碍中的作用。项目1，共 本计划项目资助(PPG)旨在阐明钠/钙失衡在机电过程中的作用 人诱导多能干细胞来源的心肌细胞(IPSC-)用于心衰相关功能障碍 基于CMS)的建模。该项目将首次从异种个体中分型DCM IPSC-CMS 致病变异体和基因组编辑对照。那么调节钠/钙的分子通路的作用 将在每一个IPSC-CMS中检查动态平衡，以确定与电-CMS有关的主要途径。 机械功能障碍和描述扩张型心肌病中的基因特异性机制。药物治疗细胞 然后，将使用响应和基因表达谱来定义特定于基因型的药物响应和 新的药物靶点。我们处于有利地位，可以在五年内实现项目目标。能够定义 心力衰竭中基于基因的机制和药物治疗与NIH和NHLBI的目标很好地一致 精准医学模型。

Project Summary Heart failure (HF) continues to have a major clinical and economic burden with stagnation in new therapies over the past two decades. A significant barrier to improved therapies is the incomplete understanding of the role of Na+/Ca2+ dysregulation in HF and its contribution to electrical and mechanical dysfunction. Project 1 of this Program Project Grant (PPG) aims to elucidate the role of Na+/Ca2+ dysregulation in electro-mechanical dysfunction associated with (HF) using human induced pluripotent stem cell-derived cardiomyocytes (iPSC- CMs) based modeling. The Project will first phenotype DCM iPSC-CMs from individuals with heterogeneous causative variants and genome edited controls. Then the role of molecular pathways that regulate Na+/Ca2+ homeostasis will be examined in each of the iPSC-CMs to define major pathways implicated in electro- mechanical dysfunction and delineate genotype-specific mechanisms within DCM. Drug treatment cellular responses and gene expression profiles will then be used to define genotype-specific drug responses and novel drug targets. We are well positioned to achieve the project goals within five years. The ability to define genotype-based mechanisms and drug treatments within HF is well aligned with NIH and NHLBI goals of precision medicine models.