Molecular Mechanisms of Stem Cell Engraftment

描述（由申请人提供）：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（三分之一）患有一种或多种心血管疾病（CVD）。尽管最近在药物和手术治疗方面取得了进展，但诊断后的长期生存率仍然很低，迫切需要开发新的治疗方法。临床研究表明，细胞疗法在心血管疾病的治疗中具有潜在的应用价值。然而，目前的临床结果不一致，并且显示出适度的益处。需要引起实验注意的一个主要问题是注射细胞的存活率差。阐明干细胞死亡的机制和开发新的方法来预防移植后的死亡，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至关重要。我们的长期目标是确定新的方法来改善移植后心肌中的干细胞保留和植入，从而增加心肌再生。移植后发生的第一步是细胞与组织细胞外基质的粘附。这种相互作用是由位于细胞表面的蛋白质介导的，称为整合素。在本研究中，我们将测试特异性整合素在过度表达时是否能增强心脏干细胞对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缺血心肌干细胞植入的理解，并允许直接确定增强植入与细胞治疗功能结果之间的联系。从这项资助中获得的见解可以为细胞治疗的新领域提供重大的转化进展。

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)