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Human iPSC-derived atrial cardiomyocytes to model atrial fibrillation in a dish

人 iPSC 衍生的心房心肌细胞在培养皿中模拟心房颤动

基本信息

批准号：
10548469
负责人：
Dawood Darbar
金额：
$ 2.6万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-17 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548469
关键词：
Action Potentials Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation CRISPR/Cas technology Capsid Proteins Cardiac Cardiac Myocytes Catheters Cell Culture Techniques Cell Line Cell model Cells Cessation of life Clinical Coculture Techniques Collaborations Critical Pathways Data Development Dexamethasone Disease model Electrophysiology (science)Engineering Etiology Extracellular Matrix Extracellular Matrix Proteins Failure Familial atrial fibrillation Fibroblasts Functional disorder Gap Junctions Generations Genetic Genomics Goals Heart Atrium Heart failure Heritability Heterogeneity Human Hydrogels Insulin-Like Growth Factor I Ion Channel Link Membrane Mexiletine Modeling Molecular Morbidity - disease rate Mutation Myofibroblast Pathogenesis Patient Care Patients Pattern Pharmaceutical Preparations Phenotype Play Polymers Potassium Channel Protocols documentation Research Personnel Role Signal Pathway Signaling Molecule Sodium Structural Protein System Testing Toxic effect Translating Translations Tretinoin Triiodothyronine Variant Ventricular base biobank cardiovascular pharmacology clinical care common treatment early onset gain of function gain of function mutation genetic approach human embryonic stem cell imprint improved in vivo indium arsenide individual patient induced pluripotent stem cell innovation insight kindred mortality multi-ethnic multidisciplinary novel paracrine personalized medicine polydimethylsiloxane postnatal ranolazine response skills stem cell biology stem cells stroke risk success targeted treatment

项目摘要

Project Summary Atrial fibrillation (AF) is associated with significant morbidity and increased mortality. Despite recent advances in catheter-based treatments, antiarrhythmic drugs (AADs) are still commonly used to treat AF. However, response to membrane-active drugs is highly variable, in part, because of the failure to target therapy to the underlying mechanisms. Although genetic approaches have provided important insights into the underlying mechanisms of AF, the translation of these discoveries to the bedside care of patients has been limited due to the challenges of adequately recapitulating human AF in cellular models. The ability to derive patient-specific atrial cardiomyocytes (CMs) from human induced pluripotent stem cells (iPSC)-CMs holds great promise for modeling AF-linked mutations and developing cellular models of AF that are genetically-matched to specific patients. However, atrial iPSC-CMs have not been used to elucidate the underlying cellular mechanisms of AF- linked mutations and model heritable AF. Specific Aim 1 will create the UIC Multi-Ethnic Atrial HiPSC-CM Biorepository with the goal of generating atrial iPSC-CMs from familial AF kindreds to model AF-linked mutations. Our pilot data shows that atrial iPSC-CMs recapitulated the electrophysiologic (EP) phenotype of an AF-linked SCN5A mutation, and served as a platform for targeting the underlying cellular mechanism of the gain-of-function variant. Nonetheless, enhancing the maturity of iPSC-CMs remains important as modeling mature CMs will not only provide additional insights into the underlying cellular mechanisms of AF but also identify molecular signaling pathways important for atrial development. Specific Aim 2 will test the hypothesis that the EP and structural maturity of atrial iPSC-CMs can be significantly enhanced by precise microenvironmental engineering of in-vivo relevant cell-cell, cell-extracellular matrix, and cell-soluble factor interactions, such that these cells allow for optimal modeling of AF. We will also assess the role of cardiac fibroblasts in the pathogenesis of AF and determine if they impact EP maturity by co-culturing them with atrial iPSC-CMs. Specific Aim 3 will elucidate the underlying cellular mechanisms of AF-linked mutations using atrial iPSC-CMs. We will determine the EP phenotype of an SCN5A-E428K and KCNQ1-IAP54-56 mutation using patient-specific atrial iPSC-CMs. In addition, atrial iPSC-CMs from the 2 kindreds will be genetically corrected using CRISPR-Cas9 system to definitively establish causality. Thus, the overarching goals of this proposal are to harness the complementary skills of both Co-PIs (Drs. Darbar and Khetani) to establish the UIC Multi-Ethnic Atrial HiPSC Biorepository to serve as a platform for modeling AF-linked mutations, elucidate the underlying cellular mechanisms, and identify and assess novel mechanism-based therapies for AF. This platform will not only enable a more mechanism-based approach to the treatment of AF but will also `personalize' therapy with improved efficacy and reduced toxicities for individual patients.

项目总结