Map Kinase Pathways and Anemia in the Elderly

描述（由申请人提供）：慢性疾病贫血（ACD）是老年人最常见的贫血类型之一，也是这些患者发病的常见原因。促炎细胞因子的过度产生曾被认为与该综合征的发病机制有关，但导致红细胞生成无效的确切分子机制尚不清楚。我们已经证明p38 Map激酶途径是不同骨髓抑制细胞因子对正常红细胞生成作用的共同介质，其激活对于抑制人类红细胞祖细胞的生长至关重要。我们还证明，药物抑制该途径可导致ACD患者骨髓中红细胞集落形成增强，这表明该信号级联在该综合征的病理生理中起关键作用。这项拨款申请的总体目标是确定p38通路在慢性疾病贫血发病机制中的确切作用，并确定其介导这种作用的机制。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hepcidin对正常红细胞生成的影响中的作用。具体目的B是明确ACD患者骨髓中p38通路的激活机制，并确定药物或分子抑制不同p38亚型是否能促进体外ACD骨髓中红系祖细胞的生长。这将包括使用一种新的p38抑制剂SCIO-469的研究，该抑制剂目前正在其他实体的临床开发中。具体目的C是剖析p38特异性下游效应物在抑制ACD骨髓正常红细胞生成中的作用。我们将在ACD骨髓中检测已知的p38调节激酶，如MapKapK2、MapKapKS、Msk1和Mnk1的激活情况，并确定它们对红细胞生成的抑制作用。总之，这些研究将促进我们对老年慢性贫血发病机制的全面了解，并可能为未来开发以p38和/或其效应激酶为靶点治疗ACD的新治疗方法提供基础。

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.