Localized Targeting of Matrix Proteases Following Myocardial Infarction

心肌梗塞后基质蛋白酶的局部靶向

基本信息

批准号：
8676930
负责人：
Jason A Burdick
金额：
$ 52.15万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676930
关键词：
Address Adverse event Affect Animal Model Attenuated Biological Cause of Death Cell physiology Cellular Structures Chronic Clinical Country Coupled Cytoskeleton Development Dose Enzymes Event Extracellular Matrix Failure Family suidae Feasibility Studies Feedback Fibroblasts Functional disorder Geometry Heart Heart failure Hydrogels Infarction Inhibition of Matrix Metalloproteinases Pathway Injectable Injection of therapeutic agent Intervention Left Left Ventricular Remodeling Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Modeling Myocardial Myocardial Infarction Myocardium Outcome Outcome Study Patients Peptide Hydrolases Peptides Phase Polymers Process Proteins Proteolysis Recombinants Regimen Shapes Specificity Stress System Testing Therapeutic Time Tissue Inhibitor of Metalloproteinase-3 Tissues Transgenic Organisms Translational Research Ventricular Ventricular Remodeling base clinically relevant crosslink disability innovation interstitial novel pre-clinical prevent research study response targeted delivery therapeutic target

项目摘要

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.

描述（由申请人提供）：左心室（LV）重塑是细胞和细胞外基质（ECM）事件的总结，在心肌梗死（MI）后总是发生，并且是临床结果的重要预测指标。 ECM蛋白水解酶的诱导增加，基质金属蛋白酶（MMP）发生在MI后的早期和晚期阶段，并且在此过程中，MMPS（TIMP）的组织抑制剂（TIMPS）的内源性抑制作用损失已被确定为在此过程中的生物学里程碑。尽管在MI后重塑的背景下，MMP抑制仍然是一个重要的治疗靶标，但全身传递广泛的药理学MMP抑制剂可能与不良事件有关，并且这些担忧与给药方案的困难相结合，促进了临床进展。在翻译研究环境中尚未开发的一个潜在的治疗途径是直接在MI中的TIMP的局部交付。虽然有4个已知的TIMP，但在MI后重塑的背景下，TIMP-3均匀地识别为减少。这项研究将检验中心假设：靶向放置聚合物混合凝胶，该聚合物在MI区域内提供连续的，局部的TIMP-3蛋白（RTIMP-3）的局部释放，将降低MMP蛋白水解活性，稳定ECM，稳定ECM，降低MI膨胀并有利地影响LV egotry和功能。此外，使用MMP响应性聚合物 - 凝胶构建体，该构建体将与净局部MMP蛋白水解活性相关的RTIMP-3释放RTIMP-3，将为中断ECM蛋白水解的新颖而特定的方法提供新颖而特定的方法，并减弱MI后MI重塑。这些翻译研究将提供有关局部MMP抑制对MI后重塑的直接相关决定因素的疗效的关键功能和机械结果。这些研究将提供必要的临床前信息，以进一步促进局部MMP抑制性控制的治疗途径，以中断MI后不良LV重塑的不良进展以及随后的心力衰竭发展。这个国家最常见的死亡和残疾原因之一是心脏病发作和随后的心力衰竭发展。心脏病发作后，现在很明显，MMP的长期激活继续咀嚼心脏ECM，并最终导致心脏改变形状，引起扩张和失败的过渡。这项研究将验证一种新型的治疗干预措施，以控制心脏病发作后控制MMP，从而开发创新的治疗方法，以防止心脏病发作后患者进行性心肌重塑。