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Engineering of Human Excitable Tissues from Unexcitable Cells

从不可兴奋细胞改造人类可兴奋组织

基本信息

批准号：
9046968
负责人：
Nenad Bursac
金额：
$ 44.56万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9046968
关键词：
Action Potentials Adult Aftercare Algorithms Animals Arrhythmia Biomedical Engineering Cardiac Cardiac Myocytes Cell Maturation Cell Therapy Cells Clinical Coculture Techniques Computer Simulation Connexin 43 Coupling Derivation procedure Dermal Disease Echocardiography Electrophysiology (science)Engineering Face Fibroblasts Fire - disasters Foundations Future Genes Genetic Genetic Engineering Healed Heart Heart Atrium Heart Diseases Heart failure Heterogeneity Human Human Engineering In Situ In Vitro Incidence Infarction Injection of therapeutic agent Label Maps Measurement Membrane Potentials Methods Modeling Myocardial Infarction Neonatal Nodal Optics Outcome Phenotype Pluripotent Stem Cells Potassium Channel Process Production Protocols documentation Publishing Rattus Reporter Retroviridae Sodium Channel Source Stem cells Surgical sutures System Techniques Testing Therapeutic Time Tissue Engineering Tissues Translations Transplantation Ventricular base cardiac repair cell type cellular engineering design electrical property engineering design functional outcomes gene therapy genetic manipulation healing implantation improved in vitro Assay in vivo induced pluripotent stem cell novel novel strategies overexpression preclinical study pressure public health relevance research study scale up screening sensor tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Stem cell injections into the heart are actively being pursued as a potential therapy for myocardial infarction and heart failure. While the ongoing trials with adult-derived stem cells show moderate clinical benefits, significant progress in the field is expected to arise from the use of cardiomyocytes derived from induced pluripotent stem cells. Despite great promise, eventual clinical use of pluripotent stem cell-derived cardiomyocytes faces a number of challenges that need to be resolved including key issues with inadequate cell maturation, phenotypic heterogeneity, arrhythmogenesis, low viability after implantation, and scale-up. Therefore, in this project we aim to establish a novel approach for cardiac cell and gene therapy that does not rely on the use of stem cells. Instead we propose to employ in vitro or in situ genetic engineering of fibroblasts into electrically active cells with customizable electrical phenotype that can couple with surrounding cardiomyocytes and improve their electrical and contractile function. Specifically, in Aim 1 we will utilize minimum st of genetic manipulations to rapidly and efficiently convert adult human fibroblasts into a readily expandable and homogeneous source of excitable cells that autonomously fire and conduct action potentials. In Aim 2, engineered fibroblasts with select electrophysiological phenotypes will be characterized for their functional interactions with neonatal rat cardiomyocytes in well-controlled in vitro co- culture systems. In Aim 3, we will establish if contractile function of infarcted rat hearts can be improved by implantation of engineered excitable fibroblasts or retroviral conversion of endogenous fibroblasts into electrically active cells. In addition to abov experimental studies, we will utilize computer simulations to facilitate genetic engineering of excitable cells and enhance mechanistic understanding of their functional interactions with native cardiomyocytes in vitro and in vivo. We believe that the proposed genetic and tissue engineering approach will provide strong foundation for the future experimental and clinical use of engineered fibroblasts in cell- and gene-based therapies for cardiac infarction and arrhythmias.