THE EFFECTS OF MYOFIBROBLASTS ON ELECTROMECHANICAL FUNCTION OF MODEL HEART TISSUE

肌成纤维细胞对模型心脏组织机电功能的影响

• 批准号: 8466364
• 负责人: Elliot L. Elson
• 金额: $ 47.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466364
• 关键词: Accounting; Architecture; Arrhythmia; Behavior; Biophysics; Cardiac; Cardiac Myocytes; Cells; Chickens; Computer Simulation; Coupled; Coupling; Data; Electrophysiology (science); Engineering; Experimental Models; Extracellular Matrix; Fibroblasts; Fibrosis; Fluorescent Dyes; Goals; Heart; Heart Diseases; Hypertension; In Vitro; Infarction; Measurement; Measures; Mechanics; Methods; Modeling; Molecular; Mus; Muscle Cells; Myocardial Contraction; Myocardial Infarction; Myocardium; Myofibroblast; Outcome; Pattern; Phenotype; Process; Property; Proteins; Spatial Distribution; Specific qualifier value; Sudden Death; Testing; Therapeutic; Tissue Engineering; Tissue Model; Tissues; Vision; Work; base; cell type; design; embryo cell; embryonic stem cell; engineering design; experience; heart electrical activity; heart function; hypertensive heart disease; interstitial; mechanical behavior; model design; predictive modeling; response; simulation; therapy design

DESCRIPTION (provided by applicant): Hypertension or myocardial infarction converts normal, relatively quiescent fibroblasts to a larger more contractile phenotype, the myofibroblast (mFB). The mFBs disarrange and interrupt the normal well-organized cardiac muscle, stiffening it and distorting progression of the electrical impulse that triggers orderly contraction of the heart, causing reentrant arrhythmias sometimes leading to sudden death. To understand how to avert or alleviate this consequence, it is important to know how mFBs influence the electromechanical function of the heart. The overall purpose of this work is to gain an understanding of how mFBs perturb this function using computational and experimental models designed specifically for this purpose. The outcome will be experimental and computational models for the effects of mFBs on the electrical and mechanical function of an engineered heart muscle model. The combination of electrical and mechanical function as well as computational and experimental models will exceed the range and detail of current models of cardiac fibrosis. The resulting predictive model will assist in the design of therapies for fibrosis induced by hypertensive heart disease and myocardial infarction. This work is based on the hypotheses that (1) degradation of contractile function in fibrotic myocardium results from coupled electrical and mechanical effects associated with mFB, their remodeling of ECM, and their connectivity to cardiomyocytes (CM), and (2)Accounting for the electrical interactions of CM and mFB, the triggering of CM contraction and the viscoelastic properties of cells and ECM, we can determine the effects of mFB on the electrical and mechanical function of engineered heart tissues (EHTs) and, therefore, to a useful approximation, in heart muscle. For example, delay or fragmentation of the spread of excitation is directly related to a corresponding prolongation or fragmentation of the contractile twitch response. The computational and experimental models that we are developing are designed specifically to test this hypothesis. The computational model accounts at the cellular level for the coupling of the heart's electrical activity to its mechanical behavio, including the effects of mFBs in both electrical and mechanical functions. This model will be refined with reference to experimental measurements carried out on engineered heart tissues (EHTs) assembled with specified ratios of mFBs to cardiomyocytes (CMs) and prescribed spatial patterns of mFBs. Work will proceed through a recursive process by which the experimental model will test the computational model, and the computational model will suggest designs for EHTs that specifically demonstrate the effects of mFB-CM interactions on EHT electromechanical function.

描述（由申请人提供）：高血压或心肌梗塞将正常的，相对静止的成纤维细胞转换为更大的收缩表型，肌纤维细胞（MFB）。 MFBS混乱并打断正常组织良好的心肌，使其变硬，并扭曲电脉冲的进展，从而触发心脏有序收缩，从而导致重进入心律不齐，有时会导致猝死。要了解如何避免或减轻这种后果，重要的是要知道MFB如何影响心脏的机电功能。这项工作的总体目的是了解MFBS如何使用专门为此目的设计的计算和实验模型扰动此功能。结果将是MFB对工程心肌模型的电气和机械功能的影响的实验和计算模型。电气和机械功能以及计算和实验模型的组合将超过心脏纤维化当前模型的范围和细节。由此产生的预测模型将有助于设计由高血压心脏病和心肌梗死引起的纤维化疗法。这项工作是基于（1）纤维化心肌中收缩功能降解的假设 以及与MFB相关的机械效应，其对ECM的重塑以及它们与心肌细胞（CM）的连通性以及（2）（2）考虑CM和MFB的电气相互作用，CM收缩的触发以及细胞和ECM的粘弹性的触发，因此我们可以确定MFB对MFB对电气和机械的功能（Enogial Incormitial of Grountical internical interal interical norgure）的影响（近似，心肌。例如，激发传播的延迟或破碎与相应的延长或碎片直接相关 收缩抽搐响应。我们正在开发的计算和实验模型专门设计用于检验该假设。计算模型在细胞水平上说明了心脏的电活动与其机械行为的耦合，包括MFB在电气和机械功能中的影响。该模型将参考对具有MFBS与心肌细胞（CMS）的指定比率组装的工程心脏组织（EHT）进行的实验测量进行完善。工作将通过递归过程进行，实验模型将测试计算模型，计算模型将为EHT的设计设计，这些设计专门证明了MFB-CM相互作用对EHT机电功能的影响。