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

• 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
• 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

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.

项目摘要 心律失常性心肌病（ACM）的特征是进行性纤维曲霉的替代 心肌，心律不齐和猝死。心律失常心肌病中的纤维fibrofatty取代 通过创建非导电底物来导致心律不齐的恶化，并导致心室 功能障碍导致心力衰竭。该疾病的基础机制仍不清楚。更好 需要了解发病机理，以找到更好的临床管理选择。解决这个问题 挑战，需要可靠的物种特定模型；在这里，我们建议开发一种新型的人类模型， 这将是研究心脏纤维融合浸润的发病机理的系统。这项研究整合 工程和生物医学科学，应用组织工程，心脏生理，生物信息学和茎 细胞技术。我们的长期目标是提供一种纤维曲霉的心肌浸润模型，以调查 潜在的疾病机制将导致为患者开发急需的疗法 患有与纤维状浸润有关的心脏疾病。这个的核心目标 建议是证明心肌的纤维纤维浸润可以在3D工程中复制 心脏组织，类似于收缩性不足和模仿什么是的电生理特性 在患有ACM的患者中观察到。在我们的背景下，纤维状浸润的分子特征 工程性心脏组织模型也将进行分析。我们将以两个目标对待这一点。在目标1中，我们将 使用HIPSC从 ACM患者。我们将结合hipsc cardiomyoopytes和hipsc-审核细胞接受处理 上皮间质转变；旨在类似于ACM功能表型。在AIM 2中，利用 心外膜作为纤维状浸润的来源的作用；我们将开发3D工程心脏组织模型 使用健康供体的HIPSC浸润的心肌纤维状浸润。在这项研究中，我们提出了一种策略 基于表明纤维状浸润是由心外膜激活诱导的。 HIPSC来源的心外膜细胞 将被治疗以诱导其进一步的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相关的细胞在纤维曲霉重塑的发病机理中；我们的生理相关模型将用于 揭示纤维状浸润起始和进展的细胞细胞串扰和机制 心肌。该项目将通过领导A的发展来改善ACM患者的健康 该疾病的人类模型，并加速生物医学技术质疑疾病的应用 机制，这将有助于鉴定新的治疗靶标。