hiPSC Modeling of Restrictive Cardiomyopathy for Drug Testing

用于药物测试的限制性心肌病的 hiPSC 模型

基本信息

批准号：
10716393
负责人：
MARK MERCOLA
金额：
$ 57.24万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716393
关键词：
3-Dimensional Actins Address Affect Cardiac Cardiac Myocytes Cardiomyopathies Cessation of life Chemicals Childhood Chromatin Structure Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Dimensions Disease Disease model Effectiveness Etiology Evaluation Exhibits Fibrosis Functional disorder Gene Mutation Generations Genes Genetic Genetic Predisposition to Disease Glucose Heart Diseases Heart Transplantation Heart failure Human Hyperactivity In Vitro Investigation Modeling Molecular Mutation Myosin ATPase Myosin Heavy Chains Onset of illness Outcome Pathogenesis Pathogenicity Pathologic Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Proteins Reporting Rest Restrictive Cardiomyopathy Sarcomeres Sodium Study models Testing Therapeutic Thick Transplantation Treatment Efficacy Troponin I Troponin T Ventricular Ventricular Remodeling autosome beta-Myosin cardiac tissue engineering clinical implementation design disease phenotype drug candidate drug testing efficacy evaluation genetic variant improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor molecular phenotype stem cell model symporter therapeutic candidate therapeutic development therapeutically effective transcriptome transcriptome sequencing

项目摘要

Restrictive Cardiomyopathy (RCM) is an autosomal dominant form of cardiomyopathy characterized by profound diastolic dysfunction yet normal or near-normal ventricular dimensions, wall thickness, and systolic function. RCM patients have fewer treatment options and notably poorer outcomes than those with other forms of cardiomyopathy. This is especially true in pediatric-onset RCM, for which the only definitive therapy is heart transplantation, often in childhood. Mutations that cause RCM predominate in the sarcomere, which is the contractile unit of cardiac muscle cells. Since the dysfunction is intrinsic to cardiomyocytes, human in vitro induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are well-suited to modeling the RCM and evaluating therapeutics strategies. To date, however, there are no reported investigation of hiPSC-derived cardiomyocyte models of RCM. This proposal, therefore, seeks to use hiPSC-based models of familial, pediatric RCM to elucidate pathological features, determine whether certain mutations cause distinct pathogenetic mechanisms, and evaluate the therapeutic potential of two newly approved drugs that have shown promise for treating diastolic dysfunction in other forms of heart disease. Preliminary studies generated a patient-derived, hiPSC-based model of RCM caused by mutations in cardiac Troponin-T (TNNT2). We found that heightened Ca2+ sensitivity of force generation and increased fibrosis might underlie disease pathogenesis. Besides TNNT2, mutations in other sarcomeric mutations also cause severe pediatric RCM, and some are hypothesized to induce disease by distinct pathophysiological mechanisms. Therefore, AIM 1 of this proposal is to develop hiPSC models of RCM caused by diverse gene variants, and identify distinct and common mechanisms of contractile dysfunction. Our hypothesis is that RCM is a heterogeneous disease and distinct gene variant-specific mechanisms converge to elicit hallmark clinical features of RCM. Independently, AIM 2 is to evaluate mavacamten mecarbil and sodium-glucose cotransporter-2 inhibitors (SGLT2i) for efficacy in treating contractile dysfunction in RCM using the hiPSC models. Mavacamten and SGLT2i are newly approved for other forms of heart disease. Mavacamten, by decreasing actin-myosin cross- bridging, might be therapeutically effective for RCM independently of genetic etiology. In contrast, SGLT2 inhibitors (SGLT2i), which operate by inhibiting multiple proteins and decrease intracellular [Ca2+] in cardiomyocytes, might show selectivity for gene mutation depending on pathogenic mechanism. Characterizing the basic disease mechanisms of RCM and evaluating the efficacy of candidate therapeutics is a critical step towards improving management of this challenging disease.

限制性心肌病（RCM）是一种心肌病的常染色体显性形式，其特征是舒张功能障碍却是正常或近正常的心室尺寸，壁厚和收缩功能。 RCM患者的治疗选择较少，并且与其他形式的患者相比心肌病。在小儿发作的RCM中尤其如此，唯一的确定疗法是心脏移植，通常是在童年时期。引起RCM的突变在肌节中占主导，这是心肌细胞的收缩单位。由于功能障碍是心肌细胞固有的，因此人体体外诱导的多能干细胞（HIPSC）衍生心肌细胞非常适合对RCM进行建模和评估治疗策略。但是，迄今为止尚无报道研究RCM的HIPSC衍生心肌细胞模型。因此，这个建议寻求使用基于HIPSC的家族性，小儿RCM模型来阐明病理特征，确定某些突变是否引起不同的致病机制，并评估两种新批准的药物已经显示出有望治疗其他形式的舒张功能障碍疾病。初步研究产生了由心脏突变引起的基于患者的基于HIPSC的RCM模型 Troponin-T（TNNT2）。我们发现提高了力产生和纤维化增加的Ca2+灵敏度可能基础疾病发病机理。除TNNT2外，其他肉瘤突变中的突变也会引起严重小儿RCM，有些是通过不同的病理生理机制诱导疾病的。因此，该提案的目标1是开发由不同基因变体引起的RCM的HIPSC模型，以及确定收缩功能障碍的独特和常见机制。我们的假设是RCM是异质疾病和独特的基因变异特异性机制融合到标志性的临床 RCM的功能。独立地，目标2是评估Mavacamten Mecarbil和钠 - 葡萄糖共转运蛋白-2抑制剂（SGLT2I）使用HIPSC模型在RCM中处理收缩功能障碍的功效。 Mavacamten和 SGLT2I新批准用于其他形式的心脏病。 mavacamten，通过减少肌动蛋白肌球蛋白交叉桥接可能独立于遗传病因对RCM有效。相反，SGLT2 抑制剂（SGLT2I），通过抑制多种蛋白质并减少细胞内[Ca2+] 心肌细胞可能会根据致病机制显示基因突变的选择性。特征 RCM的基本疾病机制和评估候选疗法的功效是关键的一步致力于改善这种充满挑战的疾病的管理。