Innate Immune signal transduction specificity in inflammatory disease

炎症性疾病中的先天免疫信号转导特异性

• 批准号: 10201055
• 负责人: Derek W Abbott
• 金额: $ 31.67万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201055
• 关键词: Adaptive Immune System; Applications Grants; Bacterial Infections; Cells; Chemicals; Clinic; Clinical; Complex; Databases; Disease; Drug Targeting; Goals; Hyperactivity; Immune signaling; Immunologic Deficiency Syndromes; Inflammation; Inflammatory; Inflammatory Response; Mass Spectrum Analysis; Pathway interactions; Patients; Pharmacologic Substance; Pharmacology; Phosphotransferases; Proteins; RIPK2 gene; Signal Pathway; Signal Transduction; Specificity; System; Work; bone; chemical genetics; cytokine; dysbiosis; inhibitor/antagonist; kinase inhibitor; novel; pathogen; patient population; phosphoproteomics; response; small molecule inhibitor; success; tool

ABSTRACT The NOD2:RIPK2 complex helps a cell recognize and respond to an intracellular bacterial infection. Activation of this pathway initiates a cytokine response that helps tailor the adaptive immune system to eradicate the offending pathogen. Signaling from this complex must be precisely tailored. Too little inflammation can cause immunodeficiency that can manifest in dysbiosis while too much inflammation can manifest in inflammatory disease. Over the past decade, my lab has worked to understand this signaling system with the goal of identifying drug targets such that when the NOD2:RIPK2 complex is hyperactive and therefore hyperinflammatory, we have pharmacologic tools to inhibit it. To this end, we have now developed agents for RIPK2 that inhibit its kinase activity. These inhibitors are now at the Pre-IND stage and we anticipate filing for an IND in late 2020 or early 2021. Despite this chemical success, key questions surrounding RIPK2’s kinase activity remain. While some studies suggest that kinase activity is necessary for function, others suggest it is not. We don’t know the kinase-dependent versus kinase-independent signaling pathways that are activated or inhibited. We don’t know any bone fide RIPK2 substrates, and we don’t know which patients will particularly benefit from RIPK2 inhibition. To this end, we have developed phosphoproteomic and phospho-substrate databases utilizing mass spectrometry and chemical genetics. This grant application aims to leverage these unpublished databases to i) identify novel RIPK2 substrates, ii) identify novel RIPK2 kinase-regulated signaling pathways and iii) identify patient populations in which RIPK2 targeting might be most efficacious. Better understanding RIPK2’s kinase activity is highly significant as RIPK2 inhibitors enter the clinic over the next few years.

摘要 NOD2：RIPK2复合体帮助细胞识别和响应细胞内的细菌感染。激活 启动一种细胞因子反应，帮助定制适应性免疫系统以根除 令人不快的病原体。从这个综合体发出的信号必须经过精确的定制。太少的炎症会导致 免疫缺陷可表现为生物失调，而过多的炎症可表现为炎症 疾病。在过去的十年里，我的实验室一直在努力了解这种信号系统，目标是 识别药物靶点，使得当NOD2：RIPK2复合体过度活跃并因此 高度炎症，我们有药物工具来抑制它。为此，我们现在已经开发了用于 抑制其激酶活性的RIPK2。这些抑制剂目前处于Pre-IND阶段，我们预计将提交 在2020年底或2021年初获得IND。尽管在化学上取得了成功，但围绕RIPK2的S激酶的关键问题 活动保持不变。虽然一些研究表明，激酶活性是功能所必需的，但另一些研究表明，它确实是必需的 不。我们不知道激活或激活的是依赖于激酶的信号通路还是不依赖于激酶的信号通路。 被禁止了。我们不知道有任何骨RIPK2底物，也不知道哪些患者会特别 受益于RIPK2抑制。为此，我们开发了磷酸蛋白质组和磷酸底物。 利用质谱学和化学遗传学的数据库。这项赠款申请旨在利用这些 未发表的数据库：i)鉴定新的RIPK2底物，ii)鉴定新的RIPK2激酶调节信号 途径和iii)确定RIPK2靶向可能最有效的患者群体。更好 随着RIPK2抑制剂在接下来的几年进入临床，了解RIPK2的S激酶活性具有非常重要的意义 好几年了。