S100A1: A Novel Modulator of Myocardial Infarct Inflammation and Regeneration

描述（由申请人提供）：心肌梗死（MI）导致全功能心肌丧失是心力衰竭（HF）的主要原因（50-70%），心力衰竭在美国仍然是一个主要的健康问题。MI后不良愈合和MI尺寸扩大导致有害的心脏重塑，使受损心脏易于转变为HF。在这个阶段，没有临床治疗方法可以阻止这种下坡过程，目的是促进心肌再生和限制MI大小。因此，该提议具有直接的健康相关性，因为它将分别表征和测试新的治疗原理和靶点，以有利地调节MI后炎症和再生，最终目标是将我们的发现转化为临床。在我们以前的工作中，我们已经广泛地表征了S100 A1在心肌细胞中的细胞内作用，其作为钙（Ca 2+）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MI后HF的受损心脏。在这里，我们提出了一种新的细胞外的作用S100 A1时释放的缺血心肌作为一个局部和全身的心脏损伤信号，既有利地调节心脏愈合和促进心脏组织再生，通过一个独特的相互作用与骨髓（BM）。利用具有不同心脏S100 A1表达水平和互补生化策略的基因操作小鼠模型来特异性中和和补充MI释放的细胞外S100 A1，我们将确定损伤释放的S100 A1对MI后愈合和再生的影响，并测试外源性S100 A1的治疗效果。该提议的中心假设是心肌细胞释放的S100 A1蛋白作为内源性信号分子，其在梗死心脏中触发有利的炎症反应，并通过募集BM干细胞来改善MI后的心脏再生。具体目标是：目标1：研究心肌细胞释放的S100 A1在体内调节梗死心脏炎症反应中的局部作用，以及离体心脏S100 A1靶细胞的潜在分子机制和信号通路。目标二：确定心肌细胞释放的S100 A1在体内调节骨髓对梗死心脏再生的贡献的全身作用，并表征离体心脏外S100 A1靶细胞中的潜在分子机制和信号级联。目标3：研究外源性S100 A1作为靶点在体内调节心肌梗死后心脏愈合、再生和随后的重塑的治疗作用。 公共卫生相关性源于我们的主要目标，即表征和测试一种新的治疗心脏靶点，以改善心肌梗死后的愈合和再生，心肌梗死是美国心力衰竭（HF）的主要原因。在现阶段，没有可用于促进心脏再生以预防HF的临床治疗。

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.