Altering Myoblasts to Enhance Cardiac Implantation

描述(由申请人提供)： 心肌梗死(MI)会导致心肌梗死疤痕的形成以及远端未受损伤的心肌的不良重构。正在对细胞植入进行评估，试图将梗死疤痕转化为收缩组织，并改善心肌功能。然而，疤痕并不是理想的细胞植入环境，因此，疤痕的变化可能不会逆转非梗死心肌的重塑。这种重构是由许多有害和有益的因素之间的平衡控制的，例如激肽释放酶-激动素系统，它被认为起到保护作用。这项拟议的项目将尝试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将有益的基因产品输送到心肌：1)改善细胞在梗死瘢痕中的植入；2)限制重构。目的1将验证一种假设，即通过植入表达高水平胶原酶的成肌细胞，可以增强细胞植入瘢痕，从而增强其对心脏功能的影响。目的2将通过基因工程成肌细胞将激肽释放酶基因转移到心肌梗死后瘢痕和未损伤的心肌的假说将导致足够的激动素生成，从而有利于心肌梗死后的重塑。过表达激肽释放酶的成肌细胞将通过心内、心包和冠状动脉内注射来确定最有效的给药途径。目的3将确定当细胞植入与激肽释放酶和胶原酶过度表达的成肌细胞相结合时，是否观察到协同效应。包括我们在内的许多实验室的结果表明，多能细胞的植入为治疗心肌梗死后心力衰竭提供了一种令人兴奋的新方法。然而，在全面的临床试验是合理的之前，需要解决许多问题，包括对移植细胞呈现心脏表型的能力的担忧，移植细胞的有丝分裂能力，移植细胞与电联合体的整合，以及是否需要逆转非梗死组织中发生的重塑过程。我们实验室和其他实验室之前的研究表明，当注射到瘢痕中时，自体成肌细胞提供了有益的效果，而且这种治疗不受排斥反应的限制。拟议的研究将建立在这一模式的基础上，以解决一些剩余问题。

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.