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

项目摘要 心力衰竭（HF）仍然是一个主要的临床和经济负担，新疗法停滞不前 在过去的二十年里。改善治疗的一个重要障碍是对治疗方法的不完全理解。 Na+/Ca 2+失调在HF中的作用及其对电和机械功能障碍的贡献。项目1 本计划项目补助金（PPG）旨在阐明Na+/Ca 2+失调在电-机械 使用人诱导多能干细胞衍生的心肌细胞（iPSC-1）， CMs）的建模。该项目将首先从具有异质性的个体中对DCM iPSC-CM进行表型化。 致病变体和基因组编辑对照。然后，调节Na+/Ca 2+的分子途径的作用 将在每个iPSC-CM中检查稳态，以定义与电相关的主要途径 机械功能障碍和描绘基因型特异性机制在DCM。药物治疗细胞 然后将使用反应和基因表达谱来定义基因型特异性药物反应， 新的药物靶点我们有能力在五年内实现项目目标。能够定义 HF中基于基因型的机制和药物治疗与NIH和NHLBI的目标一致， 精准医疗模式

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.