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

描述（由申请人提供）：祖细胞（PC）疗法正在开发中，作为心肌损伤后的治疗替代方案。然而，缺血后心肌的变化可能会影响供体PC的功能和存活率，并限制这种干预的益处。因此，更好地了解损伤后心肌中PC表型和存活的调节机制是非常重要的;这可能会导致更优化的治疗。 PI先前已经表明，报告基因生物发光成像（BLI）可用于非侵入性地准确和纵向监测细胞活力。此外，我们最近开发了一种新的报告基因为基础的成像传感器，可以非侵入性监测移植的PC的生物学，使用临床适用的成像策略。 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，从而产生不利的微环境，这将影响移植PC的命运。此外，我们以前已经表明，抗氧化剂调制PC导致移植后细胞存活率增加。因此，看来氧化应激是一个很好的和相关的候选人来测试这些新的监测策略。该建议的假设是，缺血后心肌和PC之间的相互作用可以被非侵入性地监测，并且这种成像策略可以适用于临床使用。目的1将测试的假设，可以使用报告基因监测的氧化状态的PC。目的2将检验以下假设：a）移植的PC的氧化状态可以在活体中直接非侵入性地监测，和B）内源性氧化信号可以用于驱动治疗基因并优化PC的存活和功能。目的3将测试的假设，这种新的策略，以监测氧化状态的PC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.