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 This grant application aims to leverage these unpublished databases to i) identify novel RIPK2 substrates, ii) identify novel RIPK2 kinase-regulated signaling pathways and iii) identify patient populations in which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 NOD 2：RIPK 2复合物帮助细胞识别并响应细胞内细菌感染。激活 启动细胞因子反应，帮助调整适应性免疫系统，以消除 有害病原体来自这个复合体的信号必须精确地定制。太少的炎症会导致 免疫缺陷可以表现在生态失调，而太多的炎症可以表现在炎症 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，使得当NOD 2：RIPK 2复合物过度活跃时， 我们有药理学工具来抑制它。为此，我们现在已经开发了用于 抑制其激酶活性的RIPK 2。这些抑制剂目前处于Pre-IND阶段，我们预计将申请 2020年底或2021年初。尽管在化学上取得了成功，但围绕RIPK 2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是功能所必需的，但其他研究表明， 没有我们不知道激活的激酶依赖性和激酶非依赖性信号通路， 压抑我们不知道任何真正的RIPK 2底物，我们也不知道哪些患者会特别 从RIPK 2抑制中获益。为此，我们开发了磷酸化蛋白质组学和磷酸化底物 利用质谱和化学遗传学的数据库。这项拨款申请旨在利用这些 未发表的数据库，以i）鉴定新型RIPK 2底物，ii）鉴定新型RIPK 2激酶调节的信号传导 和iii）鉴定其中RIPK 2靶向可能最有效的患者群体。更好 随着RIPK 2抑制剂在未来几年进入临床，了解RIPK 2的激酶活性是非常重要的。 年