Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络

• 批准号: 10441352
• 负责人: GEORGE R DUBYAK
• 金额: $ 188.67万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-24 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441352
• 关键词: Acute; Alzheimer' s Disease; Amyloid; Apoptosis; Apoptotic; Autophagocytosis; Biochemical; Biochemistry; CASP1 gene; CASP3 gene; CASP8 gene; CASP9 gene; Caspase; Categories; Cell Death; Cell Lineage; Cell membrane; Cell physiology; Cells; Cellular biology; Chronic; Complex; Crohn' s disease; Cytolysis; DNA; Disease; Disease model; Dysmyelopoietic Syndromes; Effector Cell; Elements; Epithelial Cells; Extracellular Space; Familial Mediterranean Fever; Functional disorder; Genetic; Goals; Golgi Apparatus; Immune; Immune response; Immunologics; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Interleukin-1 beta; Investigation; Link; Literature; Lytic; Mediating; Mediator of activation protein; Membrane; Molecular; Molecular Chaperones; Multiple Sclerosis; Mus; Myeloid Cells; Myocardial Infarction; N-terminal; Necrosis; Nonlytic; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peptide Signal Sequences; Population; Production; Proteins; Publishing; Reagent; Regulation; Reporting; Secretory Vesicles; Signal Transduction; Source; Sterility; Stimulus; T-Lymphocyte; Testing; Tissues; Ulcerative Colitis; VDAC1 gene; cell killing; cell type; cytokine; extracellular; gastrointestinal; granulocyte; gut inflammation; human disease; intestinal epithelium; macrophage; microbial; mouse model; neutrophil; novel; programs; response; restraint; structural biology; trafficking

OVERALL PROGRAM PROJECT: ABSTRACT Cell death pathways have historically been characterized by the proteases that become activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase activation and, largely due to the reagents available; cell death decisions were initially thought to be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which have undergone substantial expansion in the past decade, cell death decisions and their consequences are now recognized to be much more variables. In fact, even the mechanisms of cell death have been refined. They are no longer categorized by the proteases which activate the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis - is one of the most immunologically important forms of cell death. Not only does pyroptosis kill the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most important in acute and chronic inflammation. Its secretion is implicated in rare genetic inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis, Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its subsequent study, it became clear that the amyloid-like activation of these inflammasome complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis. Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL- 1β recognized by caspases and other proteases? If IL-1β is not released through a secretory ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with pyroptosis and other regulated cell death pathways that are operative in different populations of immune effector cells. This Program Project aims to utilize cell physiology, biochemistry, structural biology, and mouse and human disease models to unravel these important questions.

总体规划项目：摘要 从历史上看，细胞死亡途径的特征是 在细胞命运决定过程中被激活。细胞凋亡是由启动子和效应子caspase定义的 激活，主要是由于可用的试剂；细胞死亡的决定最初被认为是 依赖于二进制caspase(细胞凋亡)或不依赖于caspase(所有其他)。很像 其他二元区别-如Th1与Th2 T细胞或M1与M2巨噬细胞，这 在过去十年中经历了大幅扩张，细胞死亡决定和他们的 现在人们认识到，后果的变数要大得多。事实上，即使是 细胞死亡已被提炼。它们不再按激活的蛋白酶分类 级联而不是通过效应器机制。死于死亡者的原因是 孔道形成蛋白MLKL的激活。继发性坏死是由活化的 毛孔形成蛋白DFNA5(Gasdermin E/GSDME)和松果体下垂是由激活的 致孔蛋白Gasdermin D(GSDMD)是细胞死亡的最后一种类型--松下垂-- 是免疫学上最重要的细胞死亡形式之一。上睑下垂不仅会导致死亡 在细胞中，GSDMD的激活也允许IL-1β的释放。这种细胞因子是最多的 在急性和慢性炎症中很重要。它的分泌与罕见的遗传有关 炎症性疾病，如家族性地中海热以及更常见的疾病 如心肌梗塞、阿尔茨海默病、克罗恩病和溃疡性结肠炎， 多发性硬化症和其他许多疾病。与2002年发现的炎性小体及其 随后的研究表明，这些炎性小体的淀粉样活化 复合体可促进细胞内亲IL-1β的裂解和IL-1β的释放，还可促进下睑下垂。 然而，这种生物化学缺失了IL-1β释放背后的细胞生物学。伊利怎么样了- 1半胱氨酸天冬氨酸酶和其他蛋白水解酶识别的β？如果IL-1β不是通过分泌物释放的 Er-Golgi机制，是如何被贩卖出牢房的？此版本如何与 在不同人群中可操作的上睑下垂和其他受调控的细胞死亡途径 免疫效应细胞。该计划项目旨在利用细胞生理学、生物化学、 结构生物学，以及老鼠和人类的疾病模型来解开这些重要的问题。