Peptides derived from soluble extracellular matrix for promoting improved healing following myocardial infarction

心血管疾病是美国的主要死亡原因， 可用于预防严重心肌梗死后心力衰竭功能下降的治疗选择 心肌梗死（MI）。最近一种更有前途的方法是使用脱细胞生物材料来改变重塑。 通过机械手段、生物化学手段或两者来响应。一种特殊的生物材料已经证明 成年猪心室心肌细胞外基质（ECM）在临床前研究中前景广阔， 已成功完成I期临床试验。然而，采购猪心来生产材料 可能是困难的，并且在像心脏ECM这样复杂的产品中保持一致性具有挑战性。此外，我们， 和其他人已经证明，来自早期发育时间点的ECM更具再生性， 比来自成人组织的ECM，但供应问题甚至更大的规模为年轻的心脏 产生治疗剂所必需的。我们小组最近的工作表明， 溶解的ECM可以追溯到可溶性基质中存在的一组较小的特异性ECM蛋白或肽。 鉴定和表征可溶性ECM中促进创伤后更好愈合的特异性肽组。 心肌梗死可能会导致一个更一致和可靠的治疗选择，治疗后重塑， MI.我们的假设是基于我们自己的团队和其他人的重要初步数据， 存在于早期发育年龄心脏ECM中的肽将促进更多的再生愈合反应， 成人损伤比溶解的成人心室ECM和2）通过鉴定这些肽和发育 提供方法，促进他们的持久性，同时有助于新组织的形成，我们将更有效地 修复心肌梗死后的心脏为了验证这个假设，我们将实现三个目标。在第一个目标中，我们将评估 来自胎猪心的ECM是否促进了更大的愈合和功能修复， 比成年猪心脏细胞外基质的程度。我们将通过缺血再灌注损伤诱导MI， 比较注射成人或胎儿心脏ECM之间的心脏重塑和功能。第二个目标， 我们将从心脏ECM中分离和鉴定特定的肽， 与心脏愈合和修复相关的细胞表型。我们将进行一种新的印迹培养方法， 由我们的实验室开发，以识别和表征可溶性ECM中的肽， 这些反应，综合它们，并评估已确定的片段的作用机制。在第三个目标中， 将开发用于递送可溶性心脏ECM或心脏ECM的肽衍生物的生物材料递送系统， ECM以增强再生效果的持久性并促进新组织形成， 载体材料如果成功的话，我们设想一种新的肽类疗法来治疗受伤的心脏， 更标准化，更容易制造，可能更有益，以及新的交付策略 其增强ECM/肽的持久性并促进MI后更好的愈合。

Summary: Cardiovascular disease is the leading cause of death in the United States and there are limited treatments options available for preventing the functional decline to heart failure following a significant myocardial infarction (MI). One more recent promising approach is the use of acellular biomaterials to alter the remodeling response by mechanical means, biochemical means, or both. One specific biological material that has shown great promise in pre-clinical studies is adult porcine ventricular cardiac extracellular matrix (ECM) which recently successfully completed Phase I clinical trials. However, sourcing of the porcine hearts to generate the material can be difficult and maintaining consistency in a product as complex as cardiac ECM is challenging. Further, we, and others, have demonstrated that ECM derived from earlier developmental time points is more regenerative than ECM derived from adult tissues, but supply issues are even greater for younger hearts at the scale necessary to generate a therapeutic. Recent work form our group suggests that the specific beneficial effects of solubilized ECM may be traced to a smaller set of specific ECM proteins or peptides present in the soluble matrix. Identification and characterization of the set of specific peptides in soluble ECM that promote better healing post- myocardial infarction could lead to a more consistent and reliable therapeutic option for treating remodeling post- MI. Our hypotheses, based on significant preliminary data from our own group and others, are 1) that specific peptides present in early developmental age cardiac ECM will promote a more regenerative healing response in adult injury than solubilized adult ventricular ECM and 2) that by identifying these peptides and developing delivery methods that promote their persistence while aiding in neo-tissue formation, we will more effectively repair the heart following MI. To test this hypotheses, we will carry out three aims. In the first aim we will assess whether ECM derived from fetal porcine hearts promotes improved healing and functional repair to a greater extent than adult porcine cardiac extracellular matrix. We will induce MI through ischemia-reperfusion injury and compare cardiac remodeling and function between injections of adult or fetal cardiac ECM. In the second aim, we will isolate and characterize specific peptides derived from cardiac ECM that promote regenerative phenotypes in cells relevant to cardiac healing and repair. We will carry out a novel blot culture method previously developed by our lab to identify and characterize peptides in solubilized ECM that promote specific cell responses, synthesize them and assess the mechanism of action for identified fragments. In the third aim we will develop a biomaterial delivery system for delivering soluble cardiac ECM or peptide derivatives of cardiac ECM to enhance persistence of the regenerative effects and promote neo-tissue formation, utilizing silk as the carrier material. If successful we envision a new class of peptide therapeutics for treating the injured heart that is more standardized, easier to manufacture and potentially more beneficial, as well as a new deliver strategy that enhances the persistence of the ECM/ peptides and promotes better healing following MI.