DDT and CD74 receptor activation prevent cardiac injury

 描述(由申请人提供)：拟议研究的总体目标是确定决定心脏对心肌缺血和左心室压力超负荷的反应的细胞、分子和代谢机制，以便为心血管疾病患者开发新的治疗方法。我们的研究小组发现，巨噬细胞移动抑制工厂(MIF)在缺血再灌注时由心脏分泌，激活AMP激活的蛋白激酶(AMPK)，构成保护性的自分泌-旁分泌途径。MIF的保护作用是通过细胞表面CD74受体介导的。然而，MIF具有激活趋化因子受体CXCR2/4的额外多效性作用，在病理生理应激期间可能是有害的，使其不太适合于治疗开发。我们最近发现了CD74的一个非冗余的第二配体，称为D-DOPAChrome互换酶(DDT)，它对CD74受体的选择性比MIF更高。我们的初步结果表明，心肌细胞衍生的DDT在预防缺血再灌流期间的损伤和因左室压超负荷而导致的心力衰竭方面具有重要作用。我们的化学生物学小组还设计了小分子激动剂，专门促进CD74的激活。因此，我们将研究这些试剂在心脏中的分子信号和生理作用，进而探讨它们在缺血再灌注中的治疗潜力。我们的具体目标是1)确定介导CD74下游DDT作用的信号机制，2)确定内源性心肌细胞来源的DDT在调节心脏对病理性应激反应中的作用，以及3)开发和优化CD74途径作为心脏的治疗策略。了解CD74信号对心血管疾病患者具有广泛的意义，但对心脏和潜在其他固体器官缺血易感性增加的特定个体可能具有特别重要的意义。这些患者包括那些人类MIF启动子具有常见的多态性(&gt；5%)的患者，我们已经发现这会导致MIF分泌受损和CD74依赖的AMPK在缺氧时激活。老年人也可能受益，因为MIF-CD74-AMPK轴也随着年龄的增长而受损。我们组建了一支多学科团队，在细胞代谢和信号、缺血性心脏病、MIF生物学、炎症性疾病、重组蛋白质和化学合成等领域拥有专业知识。我们已经产生了新的重组蛋白、小分子激活剂、抗体和遗传小鼠模型，使我们能够测试CD74受体激活策略是否具有保护性。因此，我们准备定义缺血性心脏病的新生物途径，并开发有可能导致心血管疾病患者新治疗策略的翻译策略。

 DESCRIPTION (provided by applicant): The overarching goal of the proposed research is to define the cellular, molecular and metabolic mechanisms determining the response of the heart to myocardial ischemia and LV pressure overload, in order to develop novel therapeutic approaches for patients with cardiovascular disease. Our group discovered that macrophage migration inhibitory factory (MIF) is secreted from the heart during ischemia-reperfusion, activating AMP- activated protein kinase (AMPK) and constituting a protective autocrine-paracrine pathway. The protective action of MIF is mediated by the cell surface CD74 receptor. However, MIF has additional pleiotropic effects to activate the chemokine receptors CXCR2/4, which may be detrimental during pathophysiological stress and render it less than ideal for therapeutic development. We have recently discovered a non-redundant second ligand for CD74 called D-dopachrome tautomerase (DDT), which is more selective than MIF for the CD74 receptor. Our initial results indicate that cardiomyocyte-derived DDT has important actions to prevent both injury during ischemic-reperfusion and heart failure consequent to LV pressure overload. Our Chemical Biology group has also designed small molecule agonists that specifically facilitate activation of CD74. Thus, we will study the molecular signaling and physiological effects of these reagents in the heart and then investigate their therapeutic potential in ischemia-reperfusion. Our specific aims are 1) to determine the signaling mechanisms that mediate DDT action downstream to CD74, 2) to determine the role of endogenous cardiomyocyte-derived DDT in regulating the response of the heart to pathological stress, and 3) to develop and optimize the CD74 pathway as a therapeutic strategy in the heart. Understanding CD74 signaling has broad implications for patients with cardiovascular disease, but might have particular significance in specific individuals who have an increased susceptibility to ischemia in the heart and potentially other solid organs. Such patients include those with a common polymorphism (>5%) in the human MIF promoter, which we have shown leads to impaired MIF secretion and CD74-dependent AMPK activation during hypoxia. The elderly might also benefit, since the MIF- CD74-AMPK axis is also impaired with aging in mice. We have assembled a multi-disciplinary team with expertise in the areas of cellular metabolism and signaling, ischemic heart disease, MIF biology, inflammatory disease, recombinant protein and chemical synthesis. We have generated novel recombinant proteins, small molecule activators, antibodies and genetic mouse models to enable us to test whether the strategy of CD74 receptor activation is protective. Thus, we are poised to define novel biological pathways in ischemic heart disease and develop translational strategies that have potential to result in new treatment strategies for patients with cardiovascular disease.