Molecular Mechanisms of Stem Cell Engraftment

描述(申请人提供)：心力衰竭是西方国家的主要死亡原因。据估计，大约有8000万美国成年人(1/3)患有一种或多种心血管疾病(CVD)。确诊后的长期存活率仍然很低，尽管最近在药物和手术治疗方面有所改进，迫切需要开发新的治疗形式。临床研究表明，基于细胞的治疗在治疗心血管疾病中具有潜在的应用价值。然而，目前的临床结果并不一致，而且显示出不大的益处。需要实验关注的一个主要问题是注射细胞的存活率很低。阐明干细胞死亡的机制和开发新的移植后预防方法，对于最大限度地发挥任何干细胞类型的心脏保护和治疗潜力是至关重要的。我们的长期目标是确定新的方法来改善干细胞在移植后在心肌中的保留和植入，从而增加心肌再生。移植后的第一个步骤之一是细胞与组织细胞外基质的黏附。这种相互作用是由定位于细胞表面的整合素蛋白介导的。在这个方案中，我们将测试特定的整合素在过表达时是否可以增强心脏干细胞与心肌细胞外基质的附着，并改善心肌的再生和功能。我们提出的目标将促进对干细胞在缺血心肌中植入的理解，并允许直接确定增强植入与细胞治疗的功能结果之间的联系。从这笔赠款中发展出来的见解可以在细胞治疗的新领域提供重大的翻译进步。 公共卫生相关性：心力衰竭是心血管疾病死亡的主要原因，也是包括高血压、糖尿病和冠状动脉疾病在内的许多慢性病的最终结果。确诊后的长期存活率仍然很低，尽管最近在药物和外科治疗方面有所改进，迫切需要开发新的治疗形式，如干细胞治疗。(摘要结束)

DESCRIPTION (provided by applicant): Heart failure is the leading cause of death in Western countries. It has been estimated that approximately 80 million American adults (1 in 3) have one or more forms of cardiovascular disease (CVD). Long-term survival after diagnosis remains poor despite recent improvements in pharmacological and surgical therapy, and development of new forms of treatment is urgently needed. Clinical studies have suggested the potential use of cell-based therapy in the treatment of CVD. However, current clinical results are inconsistent and demonstrated modest benefits. One leading issue that requires experimental attention is poor survival of injected cells. Elucidation of the mechanisms involved in stem cell death and development of new ways to prevent it upon transplantation is essential to maximize the cardioprotective and therapeutic potential of any stem cell type. Our long-term goal is to define new ways to improve stem cell retention and engraftment in the myocardium after transplantation, what can lead to increased myocardium regeneration. One of the first steps that occur after transplantation involves cell adhesion to the tissue extracellular matrix. This interaction is mediated by proteins localized on the cell surface known as integrins. In this proposal, we will test if specific integrins can enhance cardiac stem cell attachment to the myocardium extracellular matrix when overexpressed, and improve myocardium regeneration and function. Our proposed aims will advance understanding of stem cell engraftment in ischemic myocardium and allow direct determination of the link between enhanced engraftment and functional outcome of cell therapy. Insights developed from this grant could provide a significant translational advance in the new area of cell-based therapy. PUBLIC HEALTH RELEVANCE: Heart failure is the leading cause of death from cardiovascular diseases and is the end result of a number of chronic illnesses, including hypertension, diabetes, and coronary artery disease. Long-term survival after diagnosis remains poor despite recent improvements in pharmacological and surgical therapy, and development of new forms of treatment, such as stem cell therapy, is urgently needed. (End of Abstract)