Localized Targeting of Matrix Proteases Following Myocardial Infarction

描述（由申请人提供）：左心室（LV）重塑是心肌梗死（MI）后不可避免地发生的细胞和细胞外基质（ECM）事件的总和，是临床结局的重要预测因素。ECM蛋白水解酶、基质金属蛋白酶（MMPs）的诱导增加发生在MI后重塑的早期和晚期，并且MMPs的组织抑制剂（TIMPs）的内源性抑制控制的丧失已被确定为该过程中的生物学里程碑。虽然MMP抑制仍然是MI后重塑背景下的重要治疗靶点，但广谱药理学MMP抑制剂的全身递送可能与不良事件相关，并且这些问题与给药方案中的困难相结合，阻碍了临床进展。在转化研究背景下尚未开发的一种潜在治疗途径是直接在重塑MI内局部递送TIMP。虽然有4种已知的TIMP，但TIMP-3已被一致地鉴定为在MI后重塑的背景下降低。本研究将检验中心假设，即在MI区域内靶向放置聚合物-水凝胶（提供重组TIMP-3蛋白（rTIMP-3）的连续、局部释放）将降低总体MMP蛋白水解活性，稳定ECM，减少MI扩张并有利地影响LV几何形状和功能。此外，使用MMP响应性聚合物-水凝胶构建体（其将释放与净局部MMP蛋白水解活性相关的rTIMP-3）将提供中断ECM蛋白水解和减弱MI后重塑的新颖且特异的方法。这些转化研究将提供关于局部MMP抑制对MI后重塑的直接相关决定因素的功效的关键功能和机制结果。这些研究将提供必要的临床前信息，进一步推进局部MMP抑制控制的治疗途径，以中断MI后不良LV重塑的不可阻挡的进展和随后的心力衰竭发展。 在这个国家，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。在心脏病发作后，现在很清楚，MMPs的慢性激活继续咀嚼心脏ECM，并最终导致心脏改变形状，诱导扩张和向衰竭过渡。这项研究将验证一种新的治疗干预，以控制MMPs后的心脏病发作，从而开发创新的治疗方法，以防止进行性心肌重塑后的心脏病发作的患者。

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.