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 This grant application aims to leverage these unpublished databases to i) identify novel RIPK2 substrates, ii) identify novel RIPK2 kinase-regulated signaling pathways and iii) identify patient populations in which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.

抽象的 NOD2：RIPK2复合物有助于细胞识别并应对细胞内细菌感染。激活 该途径启动了细胞因子反应，该反应有助于定制自适应免疫系统以消除 令人讨厌的病原体。该复合物的信号必须精确量身定制。炎症太少会导致 可以在营养不良中表现出来的免疫缺陷，而过多的注射可能会在炎症中表现出来 疾病。在过去的十年中，我的实验室一直努力理解该信号系统的目标 识别药物靶标，以便当nod2：ripk2复合物是多动的，因此 过度炎症，我们拥有抑制它的药物工具。为此，我们现在已经开发了 RIPK2抑制其激酶活性。这些抑制剂现在处于预定阶段，我们预计会提出 在2020年末或2021年初。尽管取得了化学成功，但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，但另一些研究表明这是 不是。我们不知道激活或激活的激酶与非激酶的信号通路 抑制。我们不知道任何骨头fide ripk2底物，我们不知道哪些患者会特别 RIPK2抑制作用。为此，我们开发了磷酸化蛋白质组学和磷酸化蛋白质组学 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申请 未发表的数据库i）识别新颖的RIPK2底物，ii）识别新型RIPK2激酶调节的信号传导 途径和iii）确定RIPK2靶向可能最有效的患者人群。更好的 了解RIPK2的激酶活性非常重要，因为RIPK2抑制剂在接下来的几个中进入诊所 年。