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Novel bioengineering models to dissect cardiac cell-cell defects in arrhythmogenic cardiomyopathy

剖析致心律失常性心肌病心肌细胞缺陷的新型生物工程模型

基本信息

批准号：
10667062
负责人：
Irene Cal y Mayor-Turnbull
金额：
$ 21.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2023-04-12 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667062
关键词：
3-Dimensional Acceleration Address Adipocytes Architecture Arrhythmia Atrial Natriuretic Factor Bioinformatics Biomedical Engineering Biomedical Technology Cardiac Cardiac Myocytes Cell Differentiation process Cells Clinical Management Coupling Cues Defect Deposition Desmosomes Development Disease Disease model Electrophysiology (science)Engineering Environment Epicardium Epithelium Evaluation FGF2 gene Fatty acid glycerol esters Fibroblasts Fibrosis Gene Mutation Genes Genetic Goals Health Heart Heart Diseases Heart failure Human Impairment In Vitro Infiltration Mesenchymal Modeling Molecular Molecular Profiling Mutation Myocardial Myocardial dysfunction Myocardium Pathogenesis Pathologic Patients Phenotype Physiological Physiology Property Relaxation Reporting Role Science Source Sudden Death System Techniques Therapeutic Tissue Engineering Tissue Model Ventricular Dysfunction arrhythmogenic cardiomyopathy cardiac tissue engineering cell type cellular targeting coronary fibrosis heart function human model improved induced pluripotent stem cell lipid biosynthesis new therapeutic target novel novel strategies stem cell technology therapeutic target three-dimensional modeling transcriptomics

项目摘要

PROJECT SUMMARY Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive fibrofatty replacement of the myocardium, arrhythmias, and sudden death. Fibrofatty substitution in arrhythmogenic cardiomyopathy contributes to worsening arrhythmogenesis by creating a non-conductive substrate, and causes ventricular dysfunction leading to heart failure. The mechanisms underlying this disease are still unclear; a better understanding of the pathogenesis is needed to find better options for clinical management. To address this challenge, reliable species-specific models are needed; here we propose to develop a novel human model, that will serve as a system to study the pathogenesis of cardiac fibrofatty infiltration. This study integrates engineering and biomedical sciences, applying tissue engineering, cardiac physiology, bioinformatics and stem cell technologies. Our long-term goal is to provide a model of fibrofatty myocardial infiltration to investigate underlying disease mechanisms, which will lead to the development of greatly needed therapies for patients who suffer from cardiac diseases related to the presence of fibrofatty infiltration. The central objective of this proposal is to demonstrate that fibrofatty infiltration of the myocardium can be replicated in a 3D engineered cardiac tissue, resembling deficient contractility and altered electrophysiological properties that mimic what is observed in patients that suffer from ACM. The molecular signatures of fibrofatty infiltration in the context of our engineered cardiac tissue model will also be analyzed. We will approach this in two aims. In Aim 1 we will develop a 3D engineered cardiac tissue model of fibrofatty infiltration of the myocardium using hiPSCs from patients with ACM. We will combine hiPSC-cardiomyocytes and hiPSC-epicardial cells treated to undergo epithelial-mesenchymal transition; aiming to resemble the ACM functional phenotype. In Aim 2, exploiting the role of the epicardium as source of fibrofatty infiltration; we will develop a 3D engineered cardiac tissue model of myocardial fibrofatty infiltration using hiPSCs from healthy donors. In this study, we propose a strategy based on evidence that fibrofatty infiltration is induced from epicardial activation; hiPSC-derived epicardial cells will be treated to induce their further differentiation into fibroblasts and adipocytes. We will examine functional and structural properties, along with single-cell transcriptomics of the engineered cardiac tissue models. We expect that results from this study will advance our understanding of the contribution of specific cues from ACM-related cells in the pathogenesis of fibrofatty remodeling; our physiologically relevant model will serve to unravel the cell-cell cross-talk and mechanisms responsible for initiation and progression of fibrofatty infiltration of the myocardium. This project will improve the health of patients with ACM by leading the development of a human model of the disease and accelerating the application of biomedical technologies to interrogate disease mechanisms, which will aid in the identification of novel therapeutic targets.

项目总结