Feedback regulation of innate immune signaling at mucosal surfaces

粘膜表面先天免疫信号的反馈调节

• 批准号: 7624965
• 负责人: Derek W Abbott
• 金额: $ 27.48万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624965
• 关键词: A20 protein; Acute; Affinity Chromatography; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Asthma; Bacteria; Binding; Binding Proteins; Biochemical; Body Surface Area; Cell surface; Cells; Chronic; Colitis; Crohn' s disease; Disease; Disease susceptibility; Down-Regulation; Event; Exposure to; Failure; Feedback; Functional disorder; Genotype; Grant; Human; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory Response Pathway; Intestines; Invaded; Knockout Mice; Lead; Link; Maps; Mass Spectrum Analysis; Mucosal Immunity; Organism; Pathogenesis; Pathology; Patients; Phenotype; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Phosphotransferases; Proteins; Pyelonephritis; Regulation; Research; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Stimulus; Surface; Testing; Tissues; Toll-like receptors; Transcriptional Regulation; Ubiquitination; Up-Regulation; Viral; Virus; Work; cytokine; design; extracellular; fungus; in vivo; novel; pathogen; prevent; public health relevance; receptor; response; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): As humans, we are continuously exposed to pathogens. Our innate immune system must be able to differentiate pathogenic from nonpathogenic organisms, and it must be able to tailor an immune response to respond to that pathogenic organism. This problem is particularly acute at mucosal surfaces, an area of the body in which the surface cells are in direct contact with bacteria, fungi and viruses. A number of inflammatory disorders, including Crohn's Disease, are initiated at these mucosal surfaces when the initial innate immune response is not adequately down-regulated after the pathogen is eradicated. In this grant, we study the mechanisms that control this down-regulation at mucosal surfaces. We have found that a key anti-inflammatory protein, A20, is phosphorylated and activated by the central kinase in the NF-?B signaling pathway (IKK2). We mapped the site of phosphorylation and have shown that it is required for full A20 inhibitory activity. We generated a phospho-specific antibody against this site, and we have shown that this phosphorylation occurs in vivo in response to a number of inflammatory stimuli. Our central hypothesis is that the IKK-dependent phosphorylation of A20 leads to a novel feedback mechanism to inhibit the NF-?B response such that too much inflammation does not occur at mucosal surfaces. Failure of IKK to phosphorylate A20 may lead to inflammatory pathology such as that seen in Crohn's Disease. This grant is designed to test this hypothesis. Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens. PUBLIC HEALTH RELEVANCE Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis, and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens.

描述（由申请人提供）：作为人类，我们不断暴露于病原体。我们的先天免疫系统必须能够区分致病性与非人为生物，并且必须能够量身定制免疫反应以应对该致病生物。这个问题在粘膜表面尤其急切，粘膜表面是表面细胞直接与细菌，真菌和病毒直接接触的人体区域。当最初的先天免疫反应在根除病原体后不充分下调时，许多炎症性疾病（包括克罗恩病）将在这些粘膜表面启动。在这笔赠款中，我们研究了控制粘膜表面下调的机制。我们发现，一个关键的抗炎蛋白A20在NF-？B信号通路（IKK2）中被中央激酶磷酸化和激活。我们绘制了磷酸化的位点，并表明这是全A20活性所必需的。我们针对该位点产生了一种磷酸特异性抗体，我们已经表明，这种磷酸化是在体内发生的，这是对许多炎症刺激的响应。我们的中心假设是，A20的IKK依赖性磷酸化导致了一种新型的反馈机制抑制NF-？B反应，因此在粘膜表面不会发生过多的炎症。 IKK磷酸化A20的失败可能会导致炎症病理，例如克罗恩病在克罗恩病中。该赠款旨在检验这一假设。粘膜免疫调节对各种病毒，细菌和真菌病原体的初始免疫反应。粘膜免疫的失调是多种炎症性疾病，包括炎症性肠病，哮喘，肾盂肾炎和许多原发性免疫缺陷的引发事件。了解这种失调的发生方式将具有了解慢性炎症性疾病的病理生理学以及防止这种失调后发生病原体后发生的失调。 公共卫生相关性粘膜免疫调节对各种病毒，细菌和真菌病原体的最初免疫反应。粘膜免疫的失调是一个启动事件 各种炎症性疾病，包括炎症性肠病，哮喘，肾盂肾炎和许多原发性免疫缺陷。了解这种失调的发生方式将具有了解慢性炎症性疾病的病理生理学以及防止这种失调后发生病原体后发生的失调。