Oligomerization State and Function of the NLRP3 Inflammasome

NLRP3 炎症小体的寡聚状态和功能

• 批准号: 9099379
• 负责人: Michael R. Nichols
• 金额: $ 43.95万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099379
• 关键词: Academic Research Enhancement Awards; Address; Alzheimer' s Disease; Animal Model; Automobile Driving; Binding; Biochemical; Biological Models; Biophysics; CASP1 gene; Cell Culture Techniques; Cells; Complex; Disease; Elements; Enzymatic Biochemistry; Escherichia coli; Future; Heart Diseases; Human; Immune system; Inflammatory; Insecta; Interleukin-1 beta; Investigation; Knowledge; Lead; Mammalian Cell; Nerve Degeneration; Post-Translational Protein Processing; Process; Proteins; Recombinants; Research; Series; Students; System; Therapeutic; Viral; biophysical analysis; cytokine; improved; in vitro Model; interest; light scattering; molecular mass; outreach; pathogen; protein complex; public health relevance; research study; response; stoichiometry; targeted treatment; Academic Research Enhancement Awards; Address; Alzheimer' s Disease; Animal Model; Automobile Driving; Binding; Biochemical; Biological Models; Biophysics; CASP1 gene; Cell Culture Techniques; Cells; Complex; Disease; Elements; Enzymatic Biochemistry; Escherichia coli; Future; Heart Diseases; Human; Immune system; Inflammatory; Insecta; Interleukin-1 beta; Investigation; Knowledge; Lead; Mammalian Cell; Nerve Degeneration; Post-Translational Protein Processing; Process; Proteins; Recombinants; Research; Series; Students; System; Therapeutic; Viral; biophysical analysis; cytokine; improved; in vitro Model; interest; light scattering; molecular mass; outreach; pathogen; protein complex; public health relevance; research study; response; stoichiometry; targeted treatment

 DESCRIPTION (provided by applicant): The NLRP3 inflammasome is an important intracellular component of the mammalian innate immune system. Significant research over the last decade has vastly improved the knowledge of how the inflammasome responds to a large and diverse group of bacterial, viral, fungal, and endogenous pathogens. A key step in inflammasome activation is complex formation and oligomerization of three proteins. However, the exact oligomerization state and the relationship of this oligomerization state to inflammasome function have not yet been determined. The proposed research study described in this application will produce the three inflammasome proteins in a mammalian cell system and probe these questions. By investigating the structural mechanisms driving NLRP3 inflammasome activation, we hope to further the overall understanding of this critical component of the innate immune system and identify key elements that might be exploited for therapeutic modulation. New information on these mechanisms will have implications for the treatment of neurodegeneration, heart disease, and numerous inflammatory diseases. The proposed research study described in this application will express three recombinant inflammasome proteins in a mammalian cell system and investigate the oligomerization state of each protein. Furthermore, interactions between each protein partner and the whole ternary complex will be defined and their organization determined. Finally, we will elucidate how the higher-order oligomerization state impacts inflammasome function. The proposed studies will be a significant step forward in knowledge, will guide future investigations of this important inflammatory regulator, and will provide tremendous educational involvement and outreach for many students interested in biochemical, biophysical, and biomedical studies.

 描述（由应用程序提供）：NLRP3炎性体是哺乳动物先天免疫系统的重要细胞内成分。在过去的十年中，重大研究大大提高了人们对炎症体对大型且潜水的细菌，病毒，真菌和内源性病原体的反应的了解。炎性体激活的关键步骤是三种蛋白质的复杂形成和寡聚化。但是，尚未确定确切的寡聚状态以及这种低聚状态与炎症功能的关系。该应用中描述的拟议的研究将在哺乳动物细胞系统中产生三种炎性体蛋白，并探究这些问题。通过研究驱动NLRP3炎性体激活的结构机制，我们希望能够进一步了解先天免疫系统的关键组成部分，并确定可能探索治疗调节的关键要素。有关这些机制的新信息将对神经退行性，心脏病和多种炎症性疾病的治疗产生影响。该应用中描述的拟议的研究将在哺乳动物细胞系统中表达三种重组炎性蛋白，并研究每种蛋白质的低聚态。此外，将定义每个蛋白质伴侣与整个三元络合物之间的相互作用并确定其组织。最后，我们将阐明高阶寡聚状态如何影响炎症体功能。拟议的研究将是知识的重要一步，将指导对这一重要的炎症调节剂的未来研究，并将为许多对生物化学，生物物理和生物医学研究感兴趣的学生提供巨大的教育参与和外展。