Differentiation of Granulocytes and Macrophages

描述(申请人提供)：细胞因子激活的信号通路是参与宿主防御和炎症反应的造血细胞的产生、分化和功能激活状态的关键决定因素。这些通路既包括正向信号中间产物(包括激酶和潜伏转录因子)，也包括负反馈通路，后者将细胞的反应限制为与环境相适应的反应。我们发现了细胞因子信号转导抑制蛋白(SoCs)家族，并利用特定基因缺失的小鼠确定了它们的生理重要性，从而确定这些蛋白质是体内过度炎症反应的关键抑制因子。特别是，SOCS3被证明是关键的SOCS蛋白，抑制G-CSF和IL-6等细胞因子反应中粒细胞和巨噬细胞的形成和功能，并在维持细胞对这些细胞因子反应的适当特异性方面具有先前未被怀疑的作用。我们已经产生了几种重要的试剂，包括转基因小鼠，其中SOCS3在特定细胞类型中的作用以及SOCS3中特定结构域或相应受体的作用可以在整个动物、细胞和分子水平上确定。需要回答的主要问题是：SOCS3的不同结构域如何与不同的细胞内成分相互作用来调节信号抑制？SOCS3是如何通过这些细胞因子决定信号通路的特异性的？哪些造血细胞和非造血细胞受到SOCS3作用的影响，它们在炎症反应中的相对贡献是什么？至少在某种程度上，其他SOCS蛋白在造血细胞上是否具有与SOCS3类似的作用？回答这些问题将使我们能够更清楚地定义那些将受益于SOCS3激动剂或拮抗剂的疾病状况(炎症、自身免疫、感染、癌症化疗的骨髓移植)，以及确定用于筛选它们的最佳分子靶点。

DESCRIPTION (provided by applicant): Cytokine-activated signaling pathways are the key determinants of the production, differentiation and state of functional activation of hematopoietic cells involved in host defense and inflammatory reactions. These pathways include both positive signaling intermediates (including kinases and latent transcription factors) and negative feedback pathways that limit the responses of cells to those appropriate to the situation. Our discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins and determination of their physiological importance using specific gene-deleted mice has identified these proteins as key inhibitors of excessive inflammatory responses in vivo. In particular, SOCS3 was shown to be the critical SOCS protein inhibiting the formation and function of granulocytes and macrophages in response to cytokines like G-CSF and IL-6 and to have a previously unsuspected role in maintaining the appropriate specificity in cellular responses to these cytokines. We have generated several important reagents including genetically modified mice where the roles of SOCS3 in specific cell types and the roles of specific domains in SOCS3 or the corresponding receptors can be determined at the whole animal, cellular and molecular levels. The major questions to be answered are: How do the different domains of SOCS3 interact with different intracellular components to mediate signal suppression? How does SOCS3 determine the specificity of the signaling pathways from these cytokines? Which hematopoietic and non-hematopoietic cells are affected by the actions of SOCS3 and what are their relative contributions to the inflammatory response? Do other SOCS proteins, at least to some extent, have similar actions to SOCS3 on hematopoietic cells? Answering these questions will allow us to define more clearly those disease conditions (inflammation, autoimmunity, infections, bone marrow transplantation for cancer chemotherapy) that would benefit from the use of SOCS3 agonists or antagonists as well as defining the best molecular targets to use for their screening.