S100A1: A Novel Modulator of Myocardial Infarct Inflammation and Regeneration

描述（由申请人提供）：心肌梗死（MI）导致心肌功能完全丧失是心力衰竭（HF）的主要原因（50-70%），这在美国仍然是一个主要的健康问题。心肌梗死后的不良愈合和心肌梗死面积的扩大导致有害的心脏重塑，容易使受损的心脏转变为心力衰竭。在这个阶段，没有临床治疗方法可以阻止这种下坡路，目的是促进心肌再生和限制心肌大小。因此，这一建议具有直接的健康相关性，因为它将表征和测试一种新的治疗原则和目标，分别有利于调节心肌梗死后的炎症和再生，最终目标是将我们的研究结果转化为临床。在我们之前的工作中，我们广泛地描述了S100A1在心肌细胞中的细胞内作用，作为钙（Ca2+）循环的关键调节剂，在正常心脏中发挥非有害的正性肌力作用，并保护和拯救心肌梗死后HF损伤的心脏。在这里，我们提出了一种新的细胞外作用，当S100A1被缺血心肌释放时，它可以作为局部和全身心脏损伤的信号，通过与骨髓（BM）的独特相互作用，有利地调节心脏愈合和促进心脏组织再生。我们将利用具有不同心脏S100A1表达水平的基因操纵小鼠模型和互补的生化策略特异性中和和补充mi释放的细胞外S100A1，确定损伤释放的S100A1对mi后愈合和再生的影响，并测试外源性S100A1的治疗效果。该建议的中心假设是心肌细胞释放的S100A1蛋白作为内源性信号分子，在梗死心脏中触发有利的炎症反应，并通过招募BM干细胞改善心肌梗死后的心脏再生。具体目的如下：目的1：确定心肌细胞释放的S100A1在体内调节梗死心脏炎症反应中的局部作用，以及心脏S100A1靶细胞体内潜在的分子机制和信号通路。目的2：确定心肌细胞释放的S100A1在体内调节骨髓对梗死心脏再生的作用，并表征心脏外S100A1靶细胞体内潜在的分子机制和信号级联反应。目的3：研究外源性S100A1作为靶点在体内调节心肌梗死后心脏愈合、再生和随后的重构中的治疗作用。PUBLIC HEALTH RELEVANCE源于我们的主要目标，即表征和测试一种新的治疗性心脏靶点，以改善心肌梗死后的愈合和再生，而心肌梗死是美国心力衰竭（HF）的主要原因。现阶段，尚无临床治疗方法可促进心脏再生以预防HF。

DESCRIPTION (provided by applicant): Myocardial infarction (MI) resulting in the loss of fully functional myocardium is the major cause (50-70%) of heart failure (HF), which continues to be a major health problem in the U.S. Unfavourable post-MI healing and extended MI size lead to detrimental cardiac remodeling that prone the damage heart to transition to HF. At this stage, there are no clinical therapies available to halt this downhill course with the aim to promote myocardial regeneration and limit MI size. This proposal, accordingly, has direct health relevance as it will characterize and test a novel therapeutic principle and target, respectively, to favourably modulate post-MI inflammation and regeneration with the ultimate goal of translating our findings clinically. In our previous work, we have extensively characterized the intracellular role of S100A1 in cardiomyocytes as a critical regulator of calcium (Ca2+) cycling exerting a non-detrimental positive inotropic effect in normal hearts and protect and rescue injured hearts from post-MI HF. Here, we propose a novel extracellular role for S100A1 when released by ischemic myocardium to act as a local and systemic signal of cardiac damage both favourably modulating cardiac healing and promoting cardiac tissue regeneration through a unique interaction with the bone marrow (BM). Taking advantage of genetically manipulated mouse models with different cardiac S100A1 expression levels and complementary biochemical strategies to specifically neutralize and supplement MI-released extracellular S100A1, we will determine the impact of damage-released S100A1 on post-MI healing and regeneration and test the therapeutic effect of exogenous S100A1. The Central Hypothesis of this proposal is that cardiomyocyte-released S100A1 protein acts as an endogenous signaling molecule that triggers a favourable inflammatory response in the infarcted heart and improves cardiac regeneration post-MI through recruitment of BM stem cells. The specific aims are: Aim 1: To determine the local role of cardiomyocyte- released S100A1 to modulate the inflammatory response of the infarcted heart in vivo and the underlying molecular mechanisms and signaling pathways in cardiac S100A1 target cells ex vivo. Aim 2: To determine the systemic role of cardiomyocyte-released S100A1 to modulate bone marrow contribution to the regeneration of the infarcted heart in vivo and characterize the underlying molecular mechanisms and signaling cascades in extra-cardiac S100A1 target cells ex vivo. Aim 3: To examine the therapeutic role of exogenous S100A1 as a target to modulate cardiac healing, regeneration and subsequent remodeling after myocardial infarction in vivo. PUBLIC HEALTH RELEVANCE stems from our major aim to characterize and test a novel therapeutic cardiac target to improve healing and regeneration after myocardial infaction, which is the major reason for heart failure (HF) in the U.S. At this stage, there is no clinical therapy available to promote cardiac regeneration to prevent HF.