Altering Myoblasts to Enhance Cardiac Implantation

描述（由申请人提供）： 心肌梗死（MI）导致梗死瘢痕的形成以及远端未受损心肌的不良重塑。细胞移植正在被评估，试图将梗死瘢痕转化为收缩组织，改善心肌功能。然而，瘢痕不是细胞植入的理想环境，并且瘢痕中的结果变化可能不会逆转非梗死心肌的重塑。 这种重塑是由许多有害和有益因素之间的平衡控制的，例如激肽释放酶-激肽系统，它被认为起着保护作用。拟议的项目将试图通过测试以下假设来改进现有的细胞植入方法：使用基因工程骨骼肌成肌细胞向心肌递送有益基因产物将：1）改善细胞植入梗死瘢痕; 2）限制重塑。目的1将检验这一假设，即细胞植入瘢痕，从而其对心脏功能的影响，可以通过植入表达胶原酶水平升高的成肌细胞来增强。目的2将检验通过基因工程成肌细胞将激肽释放酶基因转移到梗死瘢痕和未损伤心肌将导致足够的激肽产生以有利地影响MI后重塑的假设。将通过心内、心包内和冠状动脉内注射递送过表达激肽释放酶的成肌细胞，以确定最有效的给药途径。目的3将确定当将细胞植入与激肽释放酶和胶原酶过表达成肌细胞组合时是否观察到协同效应。来自包括我们在内的众多实验室的结果表明，多能细胞的植入为治疗MI后心力衰竭提供了一种令人兴奋的新方法。然而，在全面临床试验合理之前，需要解决许多问题，包括对植入细胞呈现心脏表型的能力、植入细胞的有丝分裂能力、移植细胞整合到电合胞体中的能力的担忧，以及逆转的需要。发生在非梗塞组织中的重塑过程。我们实验室和其他人以前的研究表明，自体成肌细胞在注射到疤痕中时提供了有益的效果，并且这种治疗不受排斥反应的限制。拟议的研究将以这一模式为基础，以解决一些剩余的问题。

DESCRIPTION (provided by applicant): Myocardial infarction (MI) leads to the formation of an infarct scar as well as adverse remodeling of the remote uninjured myocardium. Cellular engraftment is being evaluated in attempts to convert the infarct scar into contractile tissue and improve myocardial function. However, the scar is less than an ideal environment for cellular engraftment, and it is possible that resulting changes in the scar may not reverse the remodeling of non-infarcted myocardium. This remodeling is controlled by a balance among numerous deleterious and beneficial factors such as the kallikrein-kinin system, which has been suggested to play a protective role. The proposed project will attempt to improve upon existing approaches to cellular engraftment by testing the hypothesis that delivery of beneficial gene products to the myocardium using genetically engineered skeletal muscle myoblasts will: 1) improve cell engraftment into the infarct scar; and 2) limit remodeling. Aim 1 will test the hypothesis that cellular engraftment into the scar, and thus its effects on cardiac function, can be enhanced by implanting myoblasts expressing elevated levels of collagenase. Aim 2 will test the hypothesis that kallikrein gene transfer to the infarct scar and uninjured myocardium via genetically engineered myoblasts will result in sufficient kinin generation to favorably affect post-MI remodeling. Kallikrein over-expressing myoblasts will be delivered by intracardiac, intrapericardial and intracoronary injection to determine the most effective route of administration. Aim 3 will determine if synergistic effects are observed when combining cellular engraftment with kallikrein and collagenase over-expressing myoblasts. Results from numerous labs including ours suggest that engraftment of pluripotent cells offers an exciting new approach to the treatment of post-MI heart failure. However, numerous questions need to be addressed before full scale clinical trials are reasonable, including concerns about the ability of implanted cells to assume a cardiac phenotype, the mitotic capacity of implanted cells, integration of engrafted cells into the electrical syncitium, and the need to reverse the remodeling process that occurs in non-infarcted tissue. Previous studies in our labs and others have shown that autologous myoblasts provide a beneficial effect when injected into the scar and that this treatment is not limited by rejection. Proposed studies will build upon this model to address some of the remaining issues.