Localized Targeting of Matrix Proteases Following Myocardial Infarction

心肌梗塞后基质蛋白酶的局部靶向

• 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
• 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

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）重构是细胞和细胞外基质（ECM）事件的总和，其总是在心肌梗死（MI）后发生，并且是临床结果的重要预测因子。在心肌梗死后重塑的早期和晚期，ECM 蛋白水解酶、基质金属蛋白酶 (MMP) 的诱导增加，以及 MMP 组织抑制剂 (TIMP) 内源性抑制控制的丧失已被认为是这一过程中的生物学里程碑。虽然 MMP 抑制仍然是心肌梗死后重塑的重要治疗靶点，但广谱药理 MMP 抑制剂的全身给药可能与不良事件相关，这些担忧加上给药方案的困难，阻碍了临床进展。一种尚未在转化研究背景下开发的潜在治疗途径是直接在重塑性 MI 内局部递送 TIMP。虽然有 4 种已知的 TIMP，但 TIMP-3 已被一致认为在 MI 后重塑的背景下会减少。这项研究将测试一个中心假设，即在 MI 区域内定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 几何结构和功能。此外，使用MMP响应性聚合物水凝胶构建体将释放与净局部MMP蛋白水解活性相关的rTIMP-3，将提供一种新颖且特定的方法来中断ECM蛋白水解并减弱MI后重塑。这些转化研究将提供关于局部 MMP 抑制对 MI 后重塑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，以进一步推进局部 MMP 抑制控制的治疗途径，从而中断 MI 后不良左心室重塑和随后心力衰竭发展的不可避免的进展。 在这个国家，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。心脏病发作后，现在已经清楚，MMP 的慢性激活会继续侵蚀心脏 ECM，并最终导致心脏形状改变，导致扩张并过渡到衰竭。这项研究将验证一种控制心脏病发作后 MMP 的新型治疗干预措施，从而开发创新疗法来预防心脏病发作后患者进行性心肌重塑。