Role of SOCS proteins in host-pathogen responses

SOCS 蛋白在宿主-病原体反应中的作用

• 批准号: 6561472
• 负责人: PETER J. MURRAY
• 金额: $ 7.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561472
• 关键词: bacterial toxins; biological signal transduction; cytokine; genetic regulatory element; immunosuppressive; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; ubiquitin

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 .

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。先天免疫系统的病原体识别主要是通过保守的模式识别受体来激活反应的细胞成分，例如巨噬细胞。一个有效的结果是扩大对病原体的反应，提供病原体数量的早期控制并扩散，并将免疫系统推向自适应免疫的发展。因此，天生的免疫系统对于免疫几乎所有暴露于我们所暴露的病原体至关重要。但是，促炎反应必须仔细调节或为宿主带来可怕的后果。过度活跃的先天免疫反应的最明显后果是败血症。在这种鲜为人知的疾病中，从病原体激活的巨噬细胞产生的失控的全身细胞因子产生直接导致低血压和多器官衰竭。过度活跃的先天免疫反应在慢性炎症性疾病中也起作用。该建议的目标是研究在下调活化的巨噬细胞中，称为SOCS（细胞因子信号传导抑制剂）蛋白的新描述的分子的生物学。含SOC蛋白质的复合物是泛素E3连接酶，它们将多偶联蛋白链连接到靶蛋白上，以指导它们被蛋白质体降解。遗传和生化证据表明，对信号传导的直接抑制和促进降解都可能在SOC蛋白调节信号传导的能力中很重要。大量证据暗示了SOC蛋白在炎症反应中的关键决策中。该建议探讨了SOCS3和SOCS1在调节激活巨噬细胞中信号转导中的作用。 AIM 1将通过使用缺乏SOCS3的巨噬细胞以及在其造血系统中缺乏SOCS3的小鼠以及缺乏SOCS3的巨噬细胞来解决SOCS3在巨噬细胞失活中的作用。 AIM 2将确定病原体挑战的巨噬细胞中SOCS3的底物，以深入了解蛋白质SOCS3在失活过程中降解的靶标。 AIM 3将根据病原体挑战研究SOCS3基因的调节。这些研究将共同​​提供有关巨噬细胞功能，SOCS蛋白生物学和先天免疫反应的调节的新见解。田纳西亚州孟菲斯市的圣裘德儿童研究医院（S.