Redox control of the NLRP1 inflammasome

NLRP1 炎症小体的氧化还原控制

基本信息

批准号：
10277155
负责人：
Daniel Bachovchin
金额：
$ 51.23万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10277155
关键词：
Affect Antioxidants Autoimmune Diseases Autoimmunity Binding Biological Biological Assay CASP1 gene Cell Death Cell membrane Cells Cleaved cell Communicable Diseases Complex Data Electron Transport Enzymes Glutathione Glutathione Disulfide Goals Homeostasis Hydrogen Peroxide Hyperactivity Immune system Inflammasome Inflammatory Innate Immune System Interleukin-18 Knowledge Laboratories Leucine-Rich Repeat Link Lytic Malignant Neoplasms Mediating Metabolic stress Mitochondria Molecular Monitor Multiprotein Complexes Mutation N-terminal Natural Immunity Nucleotides Nutrient Oxidants Oxidation-Reduction Oxidative Stress Oxides Oxidoreductase Pathway interactions Patients Pattern recognition receptor Peptide Hydrolases Play Process Proteins Proteolysis Public Health Reactive Oxygen Species Reagent Reporter Research Research Project Grants Role Selenocysteine Serine Proteinase Inhibitors Signal Transduction Site Source TXN gene Testing Therapeutic Time Work base cytokine disease-causing mutation glutathione peroxidase inhibitor/antagonist marenostrin pathogen prevent recruit small molecule inhibitor stress reduction

Affect Antioxidants Autoimmune Diseases Autoimmunity Binding Biological Biological Assay CASP1 gene Cell Death Cell membrane Cells Cleaved cell Communicable Diseases Complex Data Electron Transport Enzymes Glutathione Glutathione Disulfide Goals Homeostasis Hydrogen Peroxide Hyperactivity Immune system Inflammasome Inflammatory Innate Immune System Interleukin-18 Knowledge Laboratories Leucine-Rich Repeat Link Lytic Malignant Neoplasms Mediating Metabolic stress Mitochondria Molecular Monitor Multiprotein Complexes Mutation N-terminal Natural Immunity Nucleotides Nutrient Oxidants Oxidation-Reduction Oxidative Stress Oxides Oxidoreductase Pathway interactions Patients Pattern recognition receptor Peptide Hydrolases Play Process Proteins Proteolysis Public Health Reactive Oxygen Species Reagent Reporter Research Research Project Grants Role Selenocysteine Serine Proteinase Inhibitors Signal Transduction Site Source TXN gene Testing Therapeutic Time Work base cytokine disease-causing mutation glutathione peroxidase inhibitor/antagonist marenostrin pathogen prevent recruit small molecule inhibitor stress reduction

展开

项目摘要

PROJECT SUMMARY Inflammasomes detect intracellular danger-associated signals and trigger an inflammatory form of cell death called pyroptosis. The danger signals that the related NLRP1 and CARD8 inflammasomes sense are unknown and represent a major knowledge gap. Interestingly, small-molecule inhibitors of the serine proteases DPP8 and DPP9 (DPP8/9) were recently discovered to induce a danger signal that activates the NLRP1 and CARD8 inflammasomes. However, DPP8/9 inhibitors, in contrast to other inflammasome activators, induce pyroptosis in only a fraction of sensitive cells over relatively long time periods. Thus, it is possible that the co-occurrence of a second danger signal with DPP8/9 inhibition is required for full and rapid NLRP1 and CARD8 activation. The central hypothesis of this application is that a lack of reactive oxygen species, or reductive stress, is the second danger signal required to fully activate these inflammasomes. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratory and described in the application. The long- term goal of this project is to understand why reductive stress is a danger signal that is closely monitored by the innate immune system. The immediate objective of this application is to determine the molecular mechanism by which reductive stress activates the NLRP1 and CARD8 inflammasomes. This project consists of three specific aims: 1) to characterize the impact of oxidants and antioxidants on NLRP1 and CARD8 activation; 2) to determine the mechanism of GPX1-mediated NLRP1 and CARD8 inactivation; and 3) to determine how TRX1 modulates NLRP1 activation. Successful completion of this project will fill a critical knowledge gap by showing that reductive stress is a key danger signal that activates the NLRP1 and CARD8 inflammasomes. Overall, this work holds tremendous promise to reveal a fundamental new connection between metabolic stress and innate immunity, and to eventually enable these complex inflammasomes to be harnessed for therapeutic benefit.

项目摘要炎症体检测细胞内危险相关信号，并触发细胞死亡的炎症形式称为凋亡。危险表明相关的NLRP1和Card8发炎感是未知的并代表一个主要的知识差距。有趣的是，串行蛋白酶DPP8的小分子抑制剂最近发现DPP9（DPP8/9）诱导激活NLRP1和Card8的危险信号炎症。然而，与其他炎症体激活剂相比，DPP8/9抑制剂诱导了凋亡在相对较长的时间内，只有一小部分敏感细胞。那是可能的同时出现的完全和快速的NLRP1和Card8激活需要使用DPP8/9的第二个危险信号。该应用的中心假设是缺乏活性氧或减轻应力是完全激活这些炎症的第二种危险信号。该假设已在应用程序实验室中产生并在应用程序中描述的初步数据的基础。长期该项目的术语目标是了解为什么减轻压力是由密切监视的危险信号先天免疫系统。该应用的直接目的是确定分子减轻应力激活NLRP1和CARD8炎症的机制。这个项目包括在三个特定目的中：1）表征氧化剂和抗氧化剂对NLRP1和Card8的影响激活; 2）确定GPX1介导的NLRP1和CARD8失活的机制；和3）到确定TRX1如何调节NLRP1激活。成功完成该项目将填补关键通过表明减轻压力是激活NLRP1和CARD8的关键危险信号来通过显示知识差距炎症。总体而言，这项工作具有巨大的希望，可以揭示一种基本的新联系在代谢压力和先天免疫之间，并最终使这些复杂的炎症体成为利用治疗益处。