Map Kinase Pathways and Anemia in the Elderly

描述(申请人提供)：慢性病贫血(ACD)是老年人中最常见的贫血类型之一，也是这些患者发病的常见原因之一。促炎症细胞因子的过度产生以前被认为与该综合征的发病机制有关，但导致无效红细胞生成的确切分子机制尚不清楚。我们已经证明，p38 MAPK通路是不同的骨髓抑制细胞因子对正常红细胞生成影响的共同中介，并且它的激活对于抑制人红系祖细胞的生长是必不可少的。我们还证明了对这一途径的药物抑制导致ACD患者骨髓红系集落形成增加，这表明这一信号级联在ACD综合征的病理生理中发挥了关键作用。这项拨款申请的总体目标是确定p38通路在慢性病贫血发病机制中的确切作用，并确定其介导这种影响的机制。具体目的A是确定p38在促炎细胞因子肿瘤坏死因子a(TNFa)和铁调节激素海普西丁对正常红细胞生成的影响中所起的作用。本研究的目的是明确急性髓系白血病患者骨髓中p38通路激活的机制，并确定不同p38亚型的药物抑制或分子抑制是否能在体外促进急性髓系白血病患者红系祖细胞的生长。这将包括使用一种新型的p38抑制剂SCIO-469的研究，该药物目前正在为其他实体进行临床开发。具体目的C是剖析特定的p38下游效应因子在抑制ACD骨髓正常红细胞生成中的作用。已知的p38调节的激酶如MapKapK2、MapKapKS、Msk1和Mnk1的激活将在ACD骨髓中进行检测，并将确定它们在抑制红细胞生成中的作用。综上所述，这些研究将促进我们对老年慢性贫血发病机制的全面理解，并可能为以p38和/或其效应蛋白激酶为靶点的ACD治疗的新的治疗方法的发展提供基础。

DESCRIPTION (provided by applicant): The anemia of chronic disease (ACD) is one of the most common types of anemia in the elderly and a frequent cause of morbidity in these patients. Overproduction of pro-inflammatory cytokines has been previously implicated in the pathogenesis of this syndrome, but the precise molecular mechanisms that lead to ineffective erythropoiesis are not known. We have shown that the p38 Map kinase pathway is a common mediator of the effects of different myelossuppressive cytokines on normal erythropoiesis and that its activation is essential for suppression of growth of human erythroid progenitors. We have also demonstrated that pharmacological inhibition of this pathway results in enhanced erythroid colony formation from the bone marrows of patients with ACD, suggesting a key role for this signaling cascade in the pathophysiology of this syndrome. The overall goal of this grant application is to determine the precise role of the p38 pathway in the pathogenesis of the anemias of chronic disease and to identify the mechanisms by which it mediates such effects. Specific aim A is to determine the role of p38 in the generation of the effects of the pro-inflammatory cytokine tumor necrosis factor a (TNFa) and the iron-regulatory hormone hepcidin on normal erythropoiesis. Specific aim B is to define the mechanisms of activation of the p38 pathway in bone marrows from patients with ACD, and to determine whether pharmacological or molecular inhibition of different p38-isotypes enhances the growth of erythroid progenitors from ACD-bone marrows in vitro. This will include studies using a novel inhibitor of p38, SCIO-469, that is currently under clinical development for other entities. Specific aim C is to dissect the roles of specific downstream effectors of p38 in the suppression of normal erythropoiesis in ACD bone marrows. The activation of known p38-regulated kinases, such as MapKapK2, MapKapKS, Msk1, and Mnk1, will be examined in ACD bone marrows, and their contributions to the suppression of erythropoiesis will be determined. Altogether, these studies should advance our overall understanding of the pathogenesis of chronic anemias in the elderly, and may provide the basis for the future development of novel therapeutic approaches for the treatment of ACD using as targets p38 and/or its effector kinases.