Project Summary Stromal derived factor-1α (SDF-1α) rapidly increases following myocardial infarction (MI) and has been shown to increase microvascular density, reduce infarct size, inhibit border zone expansion, and attenuate adverse remodeling to preserve the ischemic cardiac tissue. However, this intrinsic upregulation is transient, and the protective function of SDF-1α quickly declines, thereby reducing the potential for tissue repair. To combat this limitation, several groups have investigated the exogenous delivery of SDF-1α. It was found that early-stage delivery of exogenous SDF-1α augmented the endogenous repair process, while late-stage increase in SDF-1α was shown to improve cardiac function. These studies motivate a therapeutic approach to provide sustained SDF-1α delivery and functional benefit, which is investigated in the parent project. Despite encouraging results from short-term exogenous SDF-1α delivery, little is known about the effects of sustained SDF-1α delivery into the myocardium following acute MI. Further investigation of these effects is an important logical extension and integral component of the parent project, as it may be completely distinct from the effects of short-term treatment with SDF-1α. Further, while single delivery of SDF-1α gene therapy is already in clinical studies and demonstrate promising results, these therapies were delivered in saline. Therefore, lingering questions remain as to whether repeated delivery of the gene therapy would further improve cardiac function. For sustained delivery of SDF-1α to enter clinical studies, additional information is necessary to better understand its effects, mechanism of action, as well as any possible adverse effects. Towards this goal, we propose an extension to Aim 3 of the parent project. There, we proposed to use the elastin-like protein-hyaluronic acid (ELP-HA) hydrogel formulation, which has been optimized in vitro for sustained SDF-1α minicircle (MC) gene release, in an in vivo preclinical assessment of cardiac function recovery. In this Diversity Supplement project, we will evaluate the in vivo vascular regeneration of the heart following MI through immunohistochemistry of cardiac tissue. To investigate possible mechanism(s) of any regeneration that we see, we will perform proteomic profiling of cytokine secretions as well as RNA sequencing (RNASeq). Finally, since SDF-1α and its receptor CXCR4 is known to play an important role in stem cell homing to the ischemic myocardium, we will investigate its chemoattractive potential to draw endogenous endothelial progenitor cells (EPCs). The results of our study will inform us not only if sustained delivery of SDF-1α is beneficial to vascular and cardiac regeneration following MI, but also the mechanism by which SDF-1α delivers its benefits. This Diversity Supplement will advance the research career of an underrepresented minority trainee towards the transition to independence.

Project Narrative Clinical trials of short-term, exogenous stromal derived factor-1α (SDF-1α) delivery into the myocardium following infarction shows modest, but encouraging results, which raises the question of whether sustained SDF- 1α delivery would enhance its benefits. Here, we propose to evaluate whether sustained delivery of SDF-1α is beneficial to vascular and cardiac regeneration following myocardial infarction, as well as the mechanism by which it delivers its benefits. Better understanding of the effects, mechanism of action, and possible adverse effects of sustained SDF-1α delivery is critical for us to harness its clinical potential to treat myocardial infarction.