Non-invasive imaging of progenitor cell fate in the ischemic myocardium

描述(由申请人提供)：祖细胞(PC)治疗正在被开发为心肌损伤后的一种替代治疗方法。然而，缺血后心肌的改变可能会影响供体PC的功能和存活率，并限制这种干预的益处。因此，更好地了解损伤后PC在心肌中的表型和存活机制是非常有意义的，这可能会导致更优化的治疗。PI已证明，报告基因生物发光成像(BLI)可用于准确、纵向、无创性地监测细胞活力。此外，我们最近开发了一种新型的基于报告基因的成像传感器，它可以使用临床适用的成像策略，非侵入性地监测移植PC的生物学。心肌损伤导致氧化应激增加，促氧化剂和抗氧化剂之间的失衡，以及炎症和细胞凋亡，创造了一个不利的微环境，将影响移植PC的命运。此外，我们之前已经证明，PC的抗氧化调节会导致移植后细胞存活率的增加。因此，氧化应激似乎是测试这些新的监测策略的一个很好的和相关的候选者。这一建议的假设是，可以无创地监测缺血后心肌与PC之间的相互作用，并且这种成像策略可以适应临床使用。目标1将检验这样一个假设，即可以使用报告基因来监测PC的氧化状态。目的2将验证这样的假设：a)移植的PC的氧化状态可以在活体中直接无创地监测，以及b)内源性氧化信号可以用来驱动治疗基因，优化PC的生存和功能。Aim 3将测试这样一种假设，即这种监测PC中氧化剂状态的新策略可以适用于大型动物。

DESCRIPTION (provided by applicant): Progenitor cell (PC) therapies are being developed as a therapeutic alternative after myocardial in- jury. However, changes in the post-ischemic myocardium may affect the functionality and survival of donor PCs and limit the benefit of this intervention. Thus, there is significant interest in better under- standing the mechanisms that regulate the phenotype and survival of PCs in the myocardium after in- jury; this will likely lead to more optimized therapies. The PI has previously shown that reporter gene bioluminescence imaging (BLI) can be used to ac- curately and longitudinally monitor cell viability noninvasively. Furthermore, we recently developed a novel reporter gene-based imaging sensor that can noninvasively monitor the biology of transplanted PCs, using a clinically applicable imaging strategy. Myocardial injury leads to increased oxidative stress, an imbalance between pro- and anti-oxidants, as well as, inflammation and apoptosis, creating a hostile microenvironment that will affect the fate of transplanted PCs. Furthermore, we have previously shown that antioxidant modulation of PCs leads to increased cell survival rates after transplantation. Thus, it appears that oxidant stress is a good and relevant candidate to test these novel monitoring strategies. The hypothesis of this proposal is that the interaction between the post-ischemic myocardium and PCs can be monitored non-invasively, and that such imaging strategies can be adapted for clinical use. Aim 1 will test the hypothesis that the oxidant status of PCs can be monitored using reporter genes. Aim 2 will test the hypothesis that a) the oxidant status of transplanted PCs can be monitored noninvasively directly in the living subject, and b) endogenous oxidant signals can be used to drive a therapeutic gene and optimize the survival and functionality of PCs. Aim 3 will test the hypothesis that this novel strategy to monitor oxidant status in PCs can be adapted for use in large animals.