S100A1: A Novel Modulator of Myocardial Infarct Inflammation and Regeneration

S100A1：心肌梗塞炎症和再生的新型调节剂

• 批准号: 7796774
• 负责人: Walter J. Koch
• 金额: $ 38.63万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-11 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796774
• 关键词: Acute; Area; Binding Proteins; Biochemical; Biological; Blood Circulation; Bone Marrow; Bone Marrow Stem Cell; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cells; Cessation of life; Clinical; Data; Environment; Excision; Failure; Fibroblasts; Goals; Healed; Health; Heart; Heart failure; Immune; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Lead; Link; Marrow; Mediating; Molecular; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Necrosis; Organism; Play; Positioning Attribute; Process; Proteins; Reaction; Role; S100A1 protein; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Staging; Stem cells; Stromal Cells; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Work; Wound Healing; angiogenesis; base; clinically relevant; cytokine; experience; extracellular; healing; improved; in vivo; injured; innovation; insight; interest; mouse model; myocardial infarct sizing; new therapeutic target; novel; novel therapeutics; prevent; public health relevance; receptor; repaired; stem; tissue regeneration

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.

描述(由申请人提供)：心肌梗死(MI)导致完全功能心肌的丧失是心力衰竭(HF)的主要原因(50%-70%)，在美国心力衰竭(HF)仍然是一个主要的健康问题。心肌梗死后不利的愈合和扩大的MI大小会导致有害的心脏重塑，从而使受损的心脏容易过渡到HF。在这个阶段，还没有临床治疗方法可以阻止这种下行过程，目的是促进心肌再生和限制心肌梗死的大小。因此，这项建议具有直接的健康相关性，因为它将分别表征和测试一种新的治疗原则和目标，以有利地调节心肌梗死后的炎症和再生，最终目标是将我们的发现转化为临床。在我们之前的工作中，我们已经广泛地表征了S100A1在心肌细胞内的作用，它是钙(Ca~(2+))循环的关键调节因子，在正常心脏中发挥无害的正性变力作用，并保护和拯救心肌梗死后心衰受损的心脏。在这里，我们提出了一个新的细胞外角色，当S100A1被缺血心肌释放时，作为心脏损伤的局部和系统信号，通过与骨髓(BM)的独特相互作用，既有利于调节心脏愈合，又促进心脏组织再生。利用具有不同心脏S100A1表达水平的转基因小鼠模型和互补的生化策略来特异性中和和补充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。这一建议的中心假设是，心肌细胞释放的S100A1蛋白作为一种内源性信号分子，在心肌梗死后触发有利的炎症反应，并通过招募骨髓干细胞促进心肌梗死后的心脏再生。其具体目的是：目的1：确定心肌细胞释放的S100A1在体内对心肌梗死后炎症反应的局部调节作用，以及体外心脏S100A1靶细胞潜在的分子机制和信号通路。目的：研究心肌细胞释放的S100A1在体内调节骨髓对心肌梗死后再生的作用，并研究S100A1体外靶细胞信号转导的分子机制。目的：探讨外源性S100A1作为靶点调控心肌梗死后心脏愈合、再生和随后的重塑的作用。与公共卫生相关的是我们的主要目标是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，这是美国心力衰竭(HF)的主要原因。在现阶段，还没有可用的临床疗法来促进心脏再生来预防心力衰竭。