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.

项目概要致心律失常性心肌病 (ACM) 的特点是进行性纤维脂肪替代心肌损伤、心律失常和猝死。致心律失常性心肌病中的纤维脂肪替代通过产生非导电基质而导致心律失常恶化，并导致心室功能障碍导致心力衰竭。这种疾病的发病机制尚不清楚；更好的需要了解发病机制才能找到更好的临床治疗选择。为了解决这个问题挑战，需要可靠的物种特异性模型；在这里我们建议开发一种新颖的人体模型，这将作为研究心脏纤维脂肪浸润发病机制的系统。这项研究整合了工程和生物医学科学，应用组织工程、心脏生理学、生物信息学和干细胞细胞技术。我们的长期目标是提供纤维脂肪心肌浸润模型来研究潜在的疾病机制，这将导致开发出患者急需的疗法患有与纤维脂肪浸润相关的心脏病的人。本次活动的中心目标该提案旨在证明心肌的纤维脂肪浸润可以在 3D 工程中复制心脏组织，类似于收缩力不足和改变的电生理特性，模仿了在患有 ACM 的患者中观察到。在我们的背景下纤维脂肪浸润的分子特征还将分析工程心脏组织模型。我们将通过两个目标来实现这一目标。在目标 1 中，我们将使用来自的 hiPSC 开发心肌纤维脂肪浸润的 3D 工程心脏组织模型 ACM 患者。我们将结合经过处理的 hiPSC 心肌细胞和 hiPSC 心外膜细胞进行上皮-间质转化；旨在类似于 ACM 功能表型。在目标 2 中，利用心外膜作为纤维脂肪浸润来源的作用；我们将开发 3D 工程心脏组织模型使用来自健康供体的 hiPSC 进行心肌纤维脂肪浸润的研究。在这项研究中，我们提出了一个策略基于纤维脂肪浸润是由心外膜激活引起的证据； hiPSC 来源的心外膜细胞将进行处理以诱导其进一步分化为成纤维细胞和脂肪细胞。我们将检查功能和结构特性，以及工程心脏组织模型的单细胞转录组学。我们期望这项研究的结果将促进我们对特定线索的贡献的理解 ACM相关细胞在纤维脂肪重塑发病机制中的作用；我们的生理相关模型将有助于揭示细胞间的相互作用以及导致纤维脂肪浸润的起始和进展的机制心肌的。该项目将通过领导开发一种药物来改善 ACM 患者的健康疾病的人体模型并加速应用生物医学技术来探究疾病机制，这将有助于识别新的治疗靶点。