Role of SOCS proteins in host-pathogen responses

描述（由申请人提供）：先天免疫反应负责早期识别和控制感染。先天免疫系统对病原体的识别主要是通过保守的模式识别受体来激活应答的细胞成分，如巨噬细胞。有效的结果是增强对病原体的反应，提供对病原体数量和传播的早期控制，并推动免疫系统向适应性免疫发展。因此，先天免疫系统对我们接触到的几乎所有病原体的免疫都是必不可少的。然而，促炎反应必须小心调节，否则会给宿主带来可怕的后果。先天免疫反应过度活跃最明显的后果就是败血症。在这种知之甚少的疾病中，病原体激活的巨噬细胞产生失控的全身细胞因子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。本研究的目的是研究一组被称为SOCS（细胞因子信号抑制因子）蛋白的新分子在下调活化巨噬细胞中的生物学作用。SOCS蛋白复合物是泛素E3连接酶，它将多泛素链连接到靶蛋白上，以指导它们被蛋白体降解。遗传和生化证据表明，直接抑制信号传导和促进降解在SOCS蛋白调节信号传导的能力中可能很重要。大量证据表明SOCS蛋白参与炎症反应中的关键决策事件。本研究提出了SOCS3和SOCS1在活化巨噬细胞中调节信号转导的作用。目的1将通过使用造血系统中缺乏SOCS3的巨噬细胞以及缺乏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，以深入了解SOCS3在失活过程中降解的蛋白质。目的3将研究SOCS3基因在应对病原体挑战时的调控。总之，这些研究将为巨噬细胞功能、SOCS蛋白生物学和先天免疫反应的调控提供新的见解。表演地点(S)（组织、城市、州）田纳西州孟菲斯市圣裘德儿童研究医院

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 .