Role of SOCS proteins in host-pathogen responses

描述(申请人提供)：先天免疫反应负责早期识别和控制感染。病原体的识别主要是通过保守的模式识别受体，激活反应的细胞成分，如巨噬细胞。一个有效的结果是放大对病原体的反应，及早控制病原体的数量和传播，并推动免疫系统朝着适应性免疫的方向发展。因此，先天免疫系统对于免疫几乎所有我们接触到的病原体都是必不可少的。然而，必须仔细调控促炎反应，否则会给宿主带来可怕的后果。过度活跃的先天免疫反应最明显的后果是败血症。在这种知之甚少的疾病中，病原体激活的巨噬细胞产生的全身性细胞因子失控直接导致低血压和多器官衰竭。过度活跃的先天免疫反应也在慢性炎症性疾病中发挥作用。这项建议的目的是研究一组新描述的分子的生物学，称为SOCS(细胞因子信号抑制蛋白)蛋白，下调激活的巨噬细胞。SOCS蛋白复合体是泛素E3连接酶，将多聚泛素链连接到靶蛋白上，引导蛋白小体对其进行降解。遗传和生化证据表明，直接抑制信号和促进降解都可能在SOCS蛋白调节信号的能力中发挥重要作用。大量证据表明，SOCS蛋白参与了炎症反应中的关键决策事件。这项建议涉及SOCS3和SOCS1在调节激活的巨噬细胞中的信号转导中的作用。目标1将通过使用缺乏SOCS3的巨噬细胞和在其造血系统中缺乏SOCS3的小鼠来解决SOCS3在巨噬细胞失活中的作用。目的2将确定SOCS3在病原体挑战的巨噬细胞中的底物，以了解在失活过程中哪些蛋白SOCS3被降解。目的3研究SOCS3基因对病原菌攻击的调控作用。总之，这些研究将为巨噬细胞功能、SOCS蛋白生物学和先天性免疫反应的调节提供新的见解。演出现场(S)(组织，城市，州)圣裘德儿童研究医院，孟菲斯，田纳西州。

DESCRIPTION (provided by applicant): The innate immune response is responsible for the early recognition and control of infection. Pathogen recognition by the innate immune system is principally via conserved pattern recognition receptors that activate the cellular components of the response such as macrophages. An effective outcome is to amplify the response to pathogens, provide early control of pathogen numbers and spread, and push the immune system toward the development of adaptive immunity. The innate immune system is therefore essential for immunity to virtually all pathogens to which we are exposed. However, the pro-inflammatory response must be carefully regulated or dire consequences result for the host. The clearest consequence of an overactive innate immune response is sepsis. In this poorly understood disease, runaway systemic cytokine production from pathogen-activated macrophages leads directly to hypotension and multiorgan failure. Overactive innate immune responses also play a role in chronic inflammatory diseases. The goals of this proposal are to investigate the biology of a new described group of molecules termed the SOCS (Suppressor of Cytokine Signaling) proteins in down-regulating activated macrophages. SOCS protein-containing complexes are ubiquitin E3 ligases that attach polyubiquitin chains to target proteins in order to direct them for degradation by the proteosome. Genetic and biochemical evidence suggest that both direct inhibition of signaling and promoting degradation are likely to be important in the ability of SOCS proteins to regulate signaling. Substantial evidence implicates SOCS proteins in key decision making events in the inflammatory response. This proposal addresses the role of SOCS3 and SOCS1 in regulating signal transduction in activated macrophages. Aim 1 will address the role of SOCS3 in macrophage deactivation through the use of macrophages that lack SOCS3 along with mice that lack SOCS3 in their hematopoietic system. Aim 2 will determine the substrates of SOCS3 in pathogen-challenged macrophages to gain insight into which proteins SOCS3 targets for degradation during deactivation. Aim 3 will investigate the regulation of the SOCS3 gene in response to pathogen challenge. Together, these studies will provide new insights into macrophage function, SOCS protein biology and the regulation of the innate immune response. PERFORMANCE SITE (S) (organization, city, state) St. Jude Children's Research Hospital, Memphis, TN .