Ubiquitination Pathways Mediating Chronic Intestinal Inflammation

介导慢性肠道炎症的泛素化途径

• 批准号: 8181588
• 负责人: Derek W Abbott
• 金额: $ 24.26万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8181588
• 关键词: Abnormal coordination; Acetylmuramyl-Alanyl-Isoglutamine; Affect; Binding; Biochemistry; Chronic; Colitis; Complex; Crohn' s disease; Data; Defect; Development; Disease; Disease susceptibility; Down-Regulation; Erlotinib; Event; Exposure to; Extravasation; Gastritis; Gefitinib; Genes; Genetic; Head; Homeostasis; Ileitis; Immune; Immunology; Individual; Inflammation; Inflammatory; Inflammatory disease of the intestine; Instruction; Lamina Propria; Ligase; Link; Lung; Manuscripts; Mediating; Modeling; Molecular; Mus; NF-kappa B; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Peptidoglycan; Permeability; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Physiological; Play; Pneumonia; Polyubiquitination; Principal Investigator; Production; Protein Kinase; Publishing; RIPK2 gene; Reagent; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Societies; Surface; Susceptibility Gene; Testing; Toll-like receptors; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Tyrosine Phosphorylation Site; Ubiquitination; Work; cost; cytokine; experience; gastrointestinal; macrophage; programs; response

Project 2, headed by Dr. Derek Abbott, will will test the alternative hypothesis that exaggerated N0D2 signaling leads to chronic intestinal inflammation. This project will investigate the dysregulation of the Nod2 gene at the molecular level. Lack of coordination between inflammatory signaling pathways influences the development of CD. We recently published that the E3 ubiquifin ligase ITCH, causes K63-linked polyubiquitinafion of RIP2, and this event downregulates active NOD2:RIP2 complexes. Mice in which Itch is genetically lost (itchy mice) develop inflammatory disease at mucosal surfaces (including intestinal inflammation). We have data showing that ITCH-/- mice develop gastritis, ileitis and colitis and that drugs that inhibit RIP2 tyrosine phosphorylation, such as tarceva and iressa, inhibit the exaggerated N0D2 responses. The central hypothesis of this project is that ITCH downregulates NOD2;RIP2-induced NFDB signaling, and that CD results when this downregulation is lost. Aim 1 will study this ITCH-induced ubiquitination event to determine the biochemistry and physiologic function of ITCH-induced RIP2 ubiquitination. In Aim 2, we will determine the role of tyrosine phosphorylation of R1P2 and the role that pharmacological inhibition of this phosphorylation plays in ITCH-induced R1P2 ubiquitination and N0D2- induced cytokine responses. In Aim 3, we will characterize the Gl inflammation of the Itchy mouse and will determine whether tarceva or iressa can alleviate chronic intestinal inflammation in these mice. Our preliminary data shows that Itchy mice have increased gastrointestinal permeability. This increased permeability allows MDP leakage into the lamina propria and causes prolonged NFkappaB activation to occur. We hypothesize that tarceva and iressa will inhibit exaggerated lamina propria N0D2 activation in the itchy mice and alleviate the chronic inflammation. The overall objective of this project is to determine the biochemistry of the ITCH:RIP2 interaction, the physiologic significance of this interaction, and most importantly, whether this interaction can be inhibited pharmacologically to ameliorate chronic intestinal inflammation. RELEVANCE (See instructions): CD affects more than 500,000 individuals in the US and incurs significant costs to society. Understanding the precise mechanisms and immune defects that cause the disease will allow us to develop better therapies and begin to develop a cure for this devastating disease.

由德里克·雅培（Derek Abbott）博士领导的项目2将检验夸大N0D2的替代假设 信号导致慢性肠炎。该项目将调查NOD2的失调 分子水平的基因。炎症信号通路之间缺乏协调会影响 CD的开发。我们最近发表了E3泛素连接酶瘙痒，引起K63连接 RIP2的多泛素属，此事件下调了Active Nod2：RIP2复合物。瘙痒的老鼠 遗传损失（发痒的小鼠）在粘膜表面发生炎症性疾病（包括肠 炎）。我们有数据表明瘙痒 - / - 小鼠患胃炎，回肠炎和结肠炎以及药物 抑制RIP2酪氨酸磷酸化，例如Tarceva和Iressa，抑制了夸张的N0D2 回答。该项目的中心假设是瘙痒下调了NOD2； RIP2诱导的NFDB 信号传导，当该下调丢失时，该CD会产生。 AIM 1将研究这种瘙痒引起的 泛素化事件以确定瘙痒诱导的RIP2的生物化学和生理功能 泛素化。在AIM 2中，我们将确定R1P2的酪氨酸磷酸化的作用以及 这种磷酸化的药理抑制作用在瘙痒诱导的R1P2泛素化和N0D2-中发挥作用 诱导细胞因子反应。在AIM 3中，我们将表征发痒的小鼠的GL炎症，并将 确定Tarceva或Iressa是否可以减轻这些小鼠的慢性肠炎。我们的 初步数据表明，发痒的小鼠胃肠道渗透性增加。这增加了 渗透率使MDP泄漏到固有层中，并导致长时间的NFKappab激活为 发生。我们假设Tarceva和Iressa将抑制夸张的层次Pramina Pramina n0d2激活 发痒的小鼠并减轻慢性炎症。该项目的总体目的是确定 瘙痒的生物化学：RIP2相互作用，这种相互作用的生理意义，大多数 重要的是，这种相互作用是否可以在药理学上抑制以改善慢性肠道 炎。 相关性（请参阅说明）： CD在美国影响500,000多人，并为社会带来了巨大的成本。了解 导致疾病的精确机制和免疫缺陷将使我们能够发展出更好的疗法 并开始为这种毁灭性疾病开发一种治愈方法。