Localized Targeting of Matrix Proteases Following Myocardial Infarction

描述（由申请人提供）：左心室（LV）重构是细胞和细胞外基质（ECM）事件的总和，这些事件总是发生在心肌梗死（MI）之后，是临床结果的重要预测指标。ECM蛋白水解酶、基质金属蛋白酶（MMPs）的诱导增加发生在心肌梗死后重构的早期和晚期，而内源性MMPs的组织抑制剂（TIMPs）抑制控制的丧失已被确定为这一过程的生物学里程碑。虽然MMP抑制仍然是心肌梗死后重构的重要治疗靶点，但广谱药理学MMP抑制剂的全身递送可能与不良事件有关，这些担忧加上给药方案的困难，阻碍了临床进展。一种潜在的治疗途径尚未在转化研究背景下开发，即直接在重构的心肌梗死中局部递送timp。虽然已知有4种timp，但TIMP-3已被一致确定在心肌梗死后重构的背景下减少。本研究将验证一个中心假设，即在心肌梗死区域定向放置聚合物水凝胶，提供持续的、局部释放重组TIMP-3蛋白（rTIMP-3），将降低整体MMP蛋白水解活性，稳定ECM，减少心肌扩张，并有利地影响左室的几何形状和功能。此外，使用MMP响应性聚合物-水凝胶结构将释放与净定位MMP蛋白水解活性相关的rTIMP-3，将提供一种新的和特定的方法来中断ECM蛋白水解和减弱心肌梗死后重构。这些转化研究将为局部MMP抑制心肌梗死后重构直接相关决定因素的功效提供关键的功能和机制结果。这些研究将为进一步推进局部MMP抑制控制的治疗途径提供必要的临床前信息，以阻断心肌梗死后不良左室重构的不可阻挡的进展和随后的心力衰竭发展。在这个国家，导致死亡和残疾的最常见原因之一是心脏病发作和随后的心力衰竭。心脏病发作后，MMPs的慢性激活会继续侵蚀心脏ECM，最终导致心脏形状改变，引起扩张并过渡到衰竭。这项研究将验证一种新的治疗干预措施来控制心脏病发作后的MMPs，从而开发创新的治疗方法来防止心脏病发作后患者的进行性心肌重构。

DESCRIPTION (provided by applicant): Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI), and is an important predictor of clinical outcomes. Increased induction of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs) occur in the early and late phases of post-MI remodeling and a loss of endogenous inhibitory control by the tissue inhibitors of MMPs (TIMPs) has been identified as a biological milestone in this process. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens, have hindered clinical progress. One potential therapeutic avenue which has yet to be developed in a translational research context is the localized delivery of TIMPs directly within the remodeling MI. While there are 4 known TIMPs, TIMP-3 has been uniformly identified to be reduced in the context of post-MI remodeling. This study will test the central hypothesis that targeted placement of a polymer-hydrogel which provides continuous, localized release of recombinant TIMP-3 protein (rTIMP-3) within the MI region will reduce overall MMP proteolytic activity, stabilize the ECM, reduce MI expansion and favorably affect LV geometry and function. Moreover, using an MMP responsive polymer-hydrogel construct which will release rTIMP-3 in relation to net localized MMP proteolytic activity, will provide a novel and specific approach to interrupt ECM proteolysis and attenuate post-MI remodeling. These translational research studies will provide pivotal functional and mechanistic results regarding efficacy of localized MMP inhibition on directly relevant determinants of post-MI remodeling. These studies will provide the essential pre-clinical information necessary to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent development of heart failure. One of the most common causes of death and disability in this country is from a heart attack and the subsequent development of heart failure. Following a heart attack, it is now clear that chronic activation of MMPs continue to chew away at the heart ECM and eventually cause the heart to change shape, inducing dilation and the transition to failure. This study will validate a novel therapeuti intervention to control MMPs following a heart attack and thereby develop innovative treatments to prevent progressive myocardial remodeling in patients after a heart attack.