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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

基本信息

批准号：
10024450
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
项目类别：
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/10024450
关键词：
Acute Alzheimer&apos 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&apos s disease Cytolysis DNA Disease Disease model Dysmyelopoietic Syndromes Effector Cell Elements Epithelial Cells Estrogen receptor positive 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 Structure T-Lymphocyte Testing Tissues Ulcerative Colitis VDAC1 gene cell killing cell type cytokine extracellular gastrointestinal granulocyte human disease inflammatory disease of the intestine intestinal epithelium macrophage microbial mouse model neutrophil novel programs response restraint structural biology trafficking

项目摘要

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.

总体方案方案：摘要