Electrophysiological and antiarrhythmic benefit of cell therapy for heart disease

细胞疗法治疗心脏病的电生理和抗心律失常益处

基本信息

批准号：
7588883
负责人：
KENNETH LAURITA
金额：
$ 38.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588883
关键词：
Action Potentials Address Arrhythmia Bone Marrow Bone Marrow Stem Cell Calcium Cardiac Cardiac Myocytes Cause of Death Cell Therapy Cell Transplants Cells Clinical Trials Congestive Heart Failure Connexin 43 Connexins Coupling Data Reporting Electrophysiology (science)Engraftment Gap Junctions Giant Cells Goals Heart Heart Diseases Homing Infarction Investigation Laboratories Maps Measures Mesenchymal Stem Cells Modeling Molecular Abnormality Muscle Cells Myoblasts Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Optics Principal Investigator Process Property Proteins Rattus Reporting Risk Safety Science Site Skeletal Muscle Stem cells Stromal Cell-Derived Factor 1 System Techniques United States base gene therapy hemodynamics improved in vivo injured novel overexpression programs sudden cardiac death tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Ischemic heart disease (IHD) is the leading cause of death in the USA and results in irreversible damage to the myocardium. Recent studies suggest that cardiac function can be restored by adding new, healthy cells such as skeletal muscle myoblasts (SKMB) or bone marrow-derived mesenchymal stem cells (MSC). Early results of cell therapy are encouraging and indicate hemodynamic improvement; however, it is unknown if cell therapy can reduce the risk of sudden cardiac death (SCO) associated with IHD. Moreover, significant safety concerns have been raised due to reports of increased arrhythmia risk. To date, several studies suggest that the ability of transplanted cells to electrically couple with host cells is an important determinant of arrhythmia risk. In addition, augmenting the natural tissue regeneration process by enhancing stem cell homing to the site of damaged myocardium may provide further benefit. In general, we hypothesize that the ability of cell therapy to reduce arrhythmia vulnerability will be determined by its ability to enhance electrophysiological viability of the infarct zone through the engraftment of viable cells that form functional electrical connections. Therefore a major goal of this proposal is to determine the electrophysiological benefit and, thus, the antiarrhythmic consequence of cell therapy for IHD, and to optimize cell therapy by enhancement of intercellular coupling and cell homing/engraftment using gene therapy. To achieve these goals, novel optical mapping techniques and a rat model of IHD will be utilized to address the following specific aims: 1) Develop and validate an optical mapping system to investigate cell therapy for SCD associated with myocardial infarction (Ml) in rat. 2) Determine the mechanisms by which cell therapy provides electrophysiological benefit or detriment in hearts with Ml. 3) Establish the antiarrhythmic or proarrhythmic mechanisms associated with cell therapy for Ml in the whole heart. 4) Determine if overexpression of connexin protein (Cx40, Cx43, and Cx45) and SDF-1 (stem cell homing factor) can significantly enhance SKMB and MSC cell therapy for SCD associated with Ml. Overall, this study will improve the understanding of the electrophysiology of cell therapy for IHD, and lay important basic groundwork for more extensive, science-based, clinical trials. The long-term goal of this study is to develop a cure for SCD associated with IHD.

描述（由申请人提供）：缺血性心脏病 (IHD) 是美国的首要死因，会对心肌造成不可逆的损害。最近的研究表明，可以通过添加新的健康细胞（例如骨骼肌成肌细胞（SKMB）或骨髓间充质干细胞（MSC））来恢复心脏功能。细胞疗法的早期结果令人鼓舞，表明血流动力学有所改善；然而，尚不清楚细胞疗法是否可以降低与 IHD 相关的心源性猝死 (SCO) 风险。此外，由于心律失常风险增加的报道，也引起了重大的安全问题。迄今为止，多项研究表明移植细胞与宿主细胞电耦合的能力是心律失常风险的重要决定因素。此外，通过增强干细胞归巢到受损心肌部位来增强自然组织再生过程可能会提供进一步的益处。一般来说，我们假设细胞疗法减少心律失常脆弱性的能力将取决于其通过植入形成功能性电连接的活细胞来增强梗塞区电生理活力的能力。因此，该提案的一个主要目标是确定 IHD 细胞治疗的电生理学益处以及抗心律失常效果，并通过使用基因治疗增强细胞间偶联和细胞归巢/植入来优化细胞治疗。为了实现这些目标，将利用新颖的光学测绘技术和IHD大鼠模型来实现以下具体目标：1)开发并验证光学测绘系统以研究与大鼠心肌梗塞(M1)相关的SCD的细胞疗法。 2)确定细胞疗法对MI心脏提供电生理学益处或损害的机制。 3)建立与全心脏M1细胞治疗相关的抗心律失常或促心律失常机制。 4)确定连接蛋白(Cx40、Cx43和Cx45)和SDF-1(干细胞归巢因子)的过表达是否可以显着增强SKMB和MSC细胞对与M1相关的SCD的治疗。总的来说，这项研究将提高对 IHD 细胞疗法电生理学的理解，并为更广泛、基于科学的临床试验奠定重要的基础。这项研究的长期目标是开发治疗与 IHD 相关的 SCD 的方法。