Map Kinase Pathways and Anemia in the Elderly

描述（由申请人提供）：慢性病贫血（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。促炎性细胞因子的过度产生以前已被牵连在这种综合征的发病机制，但导致无效的红细胞生成的确切分子机制尚不清楚。我们已经表明，p38地图激酶途径是不同的骨髓抑制细胞因子对正常红细胞生成的影响的共同调解人，它的激活是必不可少的抑制人红系祖细胞的生长。我们还证明，该途径的药理学抑制导致ACD患者骨髓中红系细胞集落形成增强，表明该信号级联在该综合征的病理生理学中起关键作用。这项资助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。具体目标A是确定p38在促炎细胞因子肿瘤坏死因子a（TNFa）和铁调节激素铁调素对正常红细胞生成的影响的产生中的作用。具体目的B是确定ACD患者骨髓中p38通路的激活机制，并确定不同p38同种型的药理学或分子抑制是否增强ACD骨髓中红系祖细胞的体外生长。这将包括使用一种新型p38抑制剂Scio-469的研究，该抑制剂目前正在为其他实体进行临床开发。具体目标C是剖析p38的特定下游效应物在ACD骨髓中正常红细胞生成的抑制中的作用。将在ACD骨髓中检查已知p38调节激酶（如MapKapK 2、MapKapKS、Msk 1和Mnk 1）的激活，并确定其对红细胞生成抑制的贡献。总之，这些研究应该推进我们的慢性贫血的发病机制在老年人的整体认识，并可能提供基础，为未来开发的新的治疗方法，用于治疗ACD使用作为目标p38和/或其效应激酶。

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.