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LV压力超负荷反应的细胞、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。本课题组发现，在缺血再灌注过程中，心脏分泌巨噬细胞移动抑制因子（MIF），激活AMP活化蛋白激酶（AMPK），构成保护性的自分泌-旁分泌通路。MIF的保护作用由细胞表面CD 74受体介导。然而，MIF具有额外的多效性作用来激活趋化因子受体CXCR 2/4，这在病理生理应激期间可能是有害的，并且使其对于治疗开发不太理想。我们最近发现了一个非冗余的第二配体的CD 74称为D-多巴色素互变异构酶（DDT），这是更有选择性的比MIF的CD 74受体。我们的初步结果表明，心肌细胞衍生的DDT具有重要的行动，以防止在缺血再灌注损伤和心力衰竭的LV压力超负荷。我们的化学生物学小组还设计了专门促进CD 74活化的小分子激动剂。因此，我们将研究这些试剂在心脏中的分子信号传导和生理作用，然后研究它们在缺血-再灌注中的治疗潜力。我们的具体目标是：1）确定介导CD 74下游DDT作用的信号传导机制，2）确定内源性心肌细胞衍生的DDT在调节心脏对病理应激反应中的作用，3）开发和优化CD 74通路作为心脏治疗策略。了解CD 74信号传导对心血管疾病患者具有广泛的意义，但可能对心脏和其他实体器官缺血易感性增加的特定个体具有特别意义。这类患者包括在人MIF启动子中具有共同多态性（>5%）的患者，我们已经证明这导致缺氧期间MIF分泌受损和CD 74依赖性AMPK活化。老年人也可能受益，因为小鼠的MIF-CD 74-AMPK轴也随着衰老而受损。我们已经组建了一个多学科的团队，在细胞代谢和信号传导，缺血性心脏病，MIF生物学，炎症性疾病，重组蛋白和化学合成领域的专业知识。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CD 74受体激活的策略是否具有保护性。因此，我们准备在缺血性心脏病中定义新的生物学途径，并开发有可能为心血管疾病患者带来新的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.