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: 10398950
• 负责人: Derek W Abbott
• 金额: $ 40.25万
• 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 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398950
• 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; 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 This grant application aims to leverage these unpublished databases to i) identify novel RIPK2 substrates, ii) identify novel RIPK2 kinase-regulated signaling pathways and iii) identify patient populations in which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.

抽象的 NOD2:RIPK2 复合物帮助细胞识别细胞内细菌感染并对其做出反应。激活 该途径的启动细胞因子反应，有助于调整适应性免疫系统以根除 致病病原体。来自该复合体的信号必须精确定制。炎症太少会导致 免疫缺陷可表现为生态失调，而过多的炎症可表现为炎症 疾病。在过去的十年里，我的实验室一直致力于了解这个信号系统，目标是 识别药物靶标，以便当 NOD2:RIPK2 复合物过度活跃时， 如果炎症过度，我们有药物工具来抑制它。为此，我们现在开发了代理 RIPK2 抑制其激酶活性。这些抑制剂目前处于预 IND 阶段，我们预计会申请 将于 2020 年底或 2021 年初进行 IND 试验。尽管取得了化学成功，但围绕 RIPK2 激酶的关键问题 活动仍然存在。虽然一些研究表明激酶活性对于功能是必需的，但其他研究表明它是 不是。我们不知道激活或激活的激酶依赖性信号通路与激酶非依赖性信号通路 抑制。我们不知道任何真正的 RIPK2 底物，也不知道哪些患者会特别喜欢 受益于 RIPK2 抑制。为此，我们开发了磷酸蛋白质组和磷酸底物 利用质谱和化学遗传学的数据库。该赠款申请旨在利用这些 未发表的数据库 i) 鉴定新型 RIPK2 底物，ii) 鉴定新型 RIPK2 激酶调节信号传导 iii) 确定 RIPK2 靶向可能最有效的患者群体。更好的 随着 RIPK2 抑制剂在接下来的几年内进入临床，了解 RIPK2 的激酶活性非常重要 年。