Injectable Hydrogels for miR302 Mimic Delivery After Myocardial Infarction

用于心肌梗塞后 miR302 模拟递送的可注射水凝胶

• 批准号: 9360559
• 负责人: Leo Le Wang
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2019-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360559
• 关键词: Adamantane; Alpha Cell; Animal Model; Biocompatible Materials; Biological; Blood; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Surgical Procedures; Catheters; Cations; Cause of Death; Cells; Cessation of life; Chemistry; Cicatrix; Clinical; Collaborations; Collection; Complex; Cyclodextrins; Deposition; Development; Down-Regulation; Drug Delivery Systems; Encapsulated; Engineering; Fellowship; Fluorescence Microscopy; Formulation; Gel; Gene Expression; Goals; Heart; Heart failure; Histology; Hospitalization; Hydrogels; Immunohistochemistry; Individual; Infarction; Inflammation; Injectable; Injection of therapeutic agent; Label; Lead; Left Ventricular Remodeling; Measures; Methodology; MicroRNAs; Mind; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial tissue; Myocardium; Names; Natural regeneration; Nutrient; Patients; Phenotype; Polyethylene Glycols; Polyethyleneimine; Polymers; Process; Prunella vulgaris; Quantitative Evaluations; RNA Interference; Rattus; Research; Research Proposals; Signal Transduction; Site; Source; Structure; Syringes; System; Technology; Therapeutic; Thinness; Time; Tissues; Training; Transfection; Treatment Efficacy; United States; Western Blotting; base; cost; design; effective therapy; experience; healing; heart cell; heart function; improved; improved outcome; inhibitor/antagonist; injured; model design; mortality; mouse model; novel; self-renewal; therapeutic target; tissue regeneration

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.

项目总结 心肌梗塞(MI)后的心力衰竭是美国发病率和死亡率的主要原因。 各州。心肌梗死涉及心肌细胞死亡、炎症和左心室重构，从而导致 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 替换丢失的心肌细胞；然而，在确定细胞来源和 将存活的心肌细胞移植到损伤的心肌中。另一种选择是诱导 保留心肌细胞以促进功能心肌的再生。我们的合作者在 Morrisey研究小组最近发现，每天全身注射miR302模拟物会导致心肌细胞 心肌梗死小鼠心肌细胞增殖及通过下调HIPPO信号促进心功能 模特。然而，这种疗法遇到了几个翻译障碍，包括偏离目标 积累、有效治疗的有限治疗时间框架以及相关的低效和费用 通过系统地输送miR302模拟物。这项提案的目标是开发一种可注射水凝胶系统。 通过将miR302局部输送到心肌梗死后的心脏组织来克服这些限制。为此，第一个目标是 这项建议的重点是开发基于阳离子聚乙烯亚胺和中性的客体-宿主组装水凝胶 聚乙二醇能(I)注射(通过注射器或导管)，(Ii)自我愈合(用于局部 在注射部位的沉积和保持)，以及(Iii)活性miR302的包覆和释放 可调节的治疗窗口。这项提议的第二个目的是将这项技术应用于一种小动物 心肌梗死模型，促进愈合，改善整体心功能。这项研究的长期目标是 开发一个平台，使用导管可释放物将各种形式的RNAi传递到MI后的心脏组织 水凝胶被设计成一种有效的药物输送系统。除了研究提案外，这项奖学金 包括一个培训计划，通过它我将获得临床经验，通过以下方式扩展我的科学背景 与Atluri和Morrisey团队合作，并在校园内外展示我的研究成果。