Injectable Hydrogels for miR302 Mimic Delivery After Myocardial Infarction

项目摘要 心肌梗死（MI）后的心力衰竭是美国心脏病发病率和死亡率的主要原因。 States. MI涉及心肌细胞死亡、炎症和左心室重塑，这导致心肌梗死。 疤痕组织的形成和心脏功能的长期丧失。一种治疗策略是选择性地 替代丢失的心肌细胞;然而，识别细胞来源存在重大挑战， 将存活的心肌细胞移植到受损的心肌中。另一种方法是诱导 剩余的心肌细胞朝向功能性心肌的再生。我们的合作者在 Morrisey小组最近表明，每日全身注射miR 302模拟物可导致心肌细胞凋亡。 增殖并通过下调小鼠中Hippo信号传导促进MI后的心脏功能 模型然而，该疗法遇到了几个翻译障碍，包括脱靶 积累，有效治疗的有限治疗时间框架，以及相关的低效率和成本 全身递送miR 302模拟物。该提案的目标是开发一种可注射的水凝胶系统 通过在MI后将miR 302局部递送至心脏组织来克服这些限制。为此，第一个目标 该提案的一个目的是开发基于阳离子聚乙烯亚胺和中性的宾主组装水凝胶 聚乙二醇能够（i）注射（通过注射器或导管流动），（ii）自愈（用于局部 沉积和保留在注射部位），和（iii）活性miR 302的包封和释放， 可调治疗窗这项提议的第二个目的是将这项技术应用于小动物身上 MI模型，以促进愈合和改善整体心脏功能。这项研究的长期目标是 开发一个平台，使用导管可递送的RNAi载体将各种形式的RNAi递送到MI后的心脏组织。 水凝胶被设计为有效药物递送系统。除了研究计划外，该奖学金 包括一个培训计划，通过该计划，我将获得临床经验，通过 我的研究成果将在校园内外展示。

PROJECT SUMMARY Heart failure following myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States. MI involves cardiomyocyte death, inflammation, and remodeling of the left ventricle, which results in the formation of scar tissue and long-term loss of heart function. One therapeutic strategy is to selectively replace lost cardiomyocytes; however, there are significant challenges to identifying a cell source and engrafting viable cardiomyocytes in the injured myocardium. An alternative is to induce the proliferation of remaining cardiomyocytes towards the regeneration of functional myocardium. Our collaborators in the Morrisey group recently showed that daily, systemic injections of miR302 mimics leads to cardiomyocyte proliferation and promotes cardiac function post-MI through down-regulation of Hippo signaling in a mouse model. However, the therapy was met with several translational impediments, including off-target accumulation, a limited therapeutic time frame for effective treatment, and the inefficiency and costs associated with systemic delivery of miR302 mimics. The goal of this proposal is to develop an injectable hydrogel system to overcome these limitations by locally delivering miR302 to cardiac tissue after MI. Towards this, the first aim of this proposal is to develop guest-host assembled hydrogels based on cationic polyethyleneimine and neutral polyethylene glycol capable of (i) injection (flow through syringe or catheter), (ii) self-healing (for local deposition and retention at the injection site), and (iii) the encapsulation and release of active miR302 over tunable therapeutic windows. The second aim of this proposal is to apply this technology in a small animal model of MI to promote healing and improved global cardiac function. The long-term goal of this research is to develop a platform to deliver various forms of RNAi to cardiac tissue post-MI using a catheter-deliverable hydrogel engineered as an effective drug delivery system. In addition to the research proposal, this fellowship includes a training plan through which I will gain clinical experience, expand my scientific background through collaboration with the Atluri and Morrisey groups, and present my research findings both on and off campus.