ANGIOGENIC TISSUE ENGINEERING TO LIMIT POST-INFARCTION VENTRICULAR REMODELING

描述（由申请人提供）：心肌缺血、梗死和心力衰竭构成了一个疾病谱系，正迅速成为全球最重要的健康挑战之一。目前的治疗重点是通过PCI和CABG进行药物优化和大血管重建。重建和替代疗法在适用性或可用性方面受到限制。一个重要的未满足的需求是微血管重建。反复的研究已经证明了强健侧支患者的生存优势。因此，存在内源性血运重建和修复机制，其益处是明确的；但其本身的效力通常是不够的。在最初的资助阶段，我们研究了内源性微血运重建的主要效应因子，内皮祖干细胞（EPC）及其强大的趋化因子基质细胞衍生因子1- α (SDF)。我们能够显著增强微血管新生，改善局部组织的生物力学特性，心室几何形状和心肌缺血损伤后的心脏功能。通过计算蛋白工程，我们设计并合成了一种超高效的SDF模拟物，并构建了一个组织工程EPC细胞外基质模拟支架，作为EPC递送系统，增强了细胞保留和存活。我们的工作要素已经扩大到临床前羊模型，并转化为最近在我们机构启动的人体临床试验。在本次修订的更新申请中，我们建议进一步深入研究sdf介导的EPC新生血管发生的特定相互作用机制，开发新的细胞因子和细胞递送平台，并在我们的临床前羊模型中提出潜在的治疗性持续释放细胞因子策略。特异性目标1将侧重于通过一种新的心脏特异性SDF条件敲除小鼠，eGFP骨髓重构和EPC跟踪，以及细胞水平灌注和生物力学改变的光学荧光定量来阐明机制见解。Specific Aim 2将开发一种创新的缓释细胞因子水凝胶复合材料和一种独特的平滑肌细胞- epc双水平细胞片，将生物支持的EPCs输送到心脏。Specific Aim 3将在微创手术方法中将水凝胶细胞因子治疗策略转化为临床前绵羊模型。我们已经产生了初步的科学组件，并汇集了团队的专业知识，希望能成功实现这些目标。

DESCRIPTION (provided by applicant): Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructive and replacement therapies are limited in applicability or availability. A significant unmet need is that of microrevascularizatio. Repeated studies have demonstrated survival advantage in patients with robust collateralization. Thus the presence of endogenous revascularization and repair mechanisms exist and the benefits are clear; but the native potency is generally inadequate. In the initial funding period, we studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha(SDF). We were able to significantly augment microvascular angiogenesis and improve local tissue biomechanical properties, ventricular geometry and cardiac function after myocardial ischemic injury. Via computational protein engineering, we then designed and synthesized a supra-efficient SDF analog as well as constructed a tissue engineered EPC extracellular-matrix simulating scaffold as an EPC delivery system that enhanced cell retention and survival. Elements of our work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this revised renewl application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, cytokine and cell delivery platforms, and advance a potential therapeutic sustained release cytokine strategy in our preclinical sheep model. Specific Aim 1 will focus on elucidating mechanistic insights via a novel cardiac-specific SDF conditional knockout mouse, eGFP marrow reconstitution and EPC tracking, and optical fluorescence quantification of cellular level perfusion and biomechanical alterations. Specific Aim 2 will develop an innovative sustained release cytokine hydrogel composite and a unique smooth muscle cell-EPC bilevel cell sheet to deliver biologically supported EPCs to the heart. Specific Aim 3 will transition the hydrogel cytokine therapeutic strategy into a preclinical sheep model in a minimally invasive operative approach. We have generated the preliminary scientific components and assembled the team expertise to hopefully successfully achieve these goals.