Cellular Engineering to identify gasdermin protein networks regulating inflammatory cell death

细胞工程鉴定调节炎症细胞死亡的gasdermin蛋白网络

• 批准号: 10024452
• 负责人: Derek W Abbott
• 金额: $ 42.78万
• 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/10024452
• 关键词: Acute; Applications Grants; Aspartate; Bacteria; Biochemical; Biochemistry; Blood Cells; CASP1 gene; CASP3 gene; Caspase; Cell Death; Cells; Cellular Membrane; Cellular biology; Cleaved cell; Clinical; Communicable Diseases; Complement; Dangerousness; Data; Development; Disease; Dysmyelopoietic Syndromes; Electrolytes; Ensure; Event; Evolution; Family; Family member; Financial compensation; Goals; Homeostasis; Human; Immune response; Immune system; Immunologics; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 beta; Membrane; Mitochondria; Myeloid Cells; Organism; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Protein Family; Proteins; Publishing; Reagent; Recording of previous events; Regulation; Role; Sampling; Shapes; Signal Transduction; Site; Stimulus; Stomach; VDAC1 gene; Virus; Work; cell killing; cell type; cellular engineering; cytokine; design; flu; hematopoietic differentiation; in vivo; leukemia; novel; pathogen; response; structural biology

Abstract Infectious bacteria and inflammatory insults can be so toxic to an organism that they require an immediate response. One such response, called pyroptosis, causes an inflammatory cell death that both alerts the immune system to the immediate threat and also ensures a continued inflammatory effort. In classical pyroptosis, Caspase-1 or Caspase-11 (Caspase-4/5 human) cleaves the pore forming protein, Gasdermin D (GSDMD). This cleaved GSDMD then oligomerizes to form a pore in cellular membranes. Gasdermin D pore formation allows the acute release of IL-1 from the cell, while also destroying membrane integrity such that mitochondrial damage and electrolyte imbalances quickly kill the cell. Implicit in this is that should pyroptosis be blocked, either genetically or pharmacologically, neutralization of the pathogen is so important to organismal survival that alternative mechanisms to initiate cytokine release and inflammatory cell death must have evolved. We are only now beginning to understand these compensatory responses and their role in shaping the immune response. Our preliminary data, with support from the preliminary data from the other three projects in this PPG application, will establish that mechanisms of compensation involve both Gasdermin redundancy and alternative protease cleavage events. We hypothesize that these compensatory mechanisms are cell-type specific. We further posit that they influence the timing and amplitude of cytokine release, the timing and inflammatory capacity of the resulting cell death and the in vivo immune response to inflammatory stimuli. The overall hypothesis of this application is that mechanisms to compensate for loss of pyroptosis alter the inflammatory and immunologic response to an inflammatory insult. We further hypothesize that this compensation helps establish myeloid cell homeostasis and that disruption of these compensatory mechanisms influences the pathologic development of Myelodysplasia and subsequent Leukemia progression. The long-term goal of this work is to better understand how pyroptotic compensatory mechanisms influence the inflammatory response and immunologic homeostasis in hopes of better understanding how to manipulate these pathways in disease.

摘要 感染性细菌和炎性损伤对生物体的毒性可能很大，因此需要立即进行治疗。 反应其中一种反应，称为焦亡，引起炎症细胞死亡，既警告 免疫系统的直接威胁，也确保了持续的炎症努力。在古典 焦亡，半胱天冬酶-1或半胱天冬酶-11（人半胱天冬酶-4/5）切割成孔蛋白Gasdermin D （GSDMD）。这种裂解的GSDMD然后寡聚化以在细胞膜中形成孔。Gasdermin D孔 形成允许IL-1从细胞中急性释放，同时也破坏膜的完整性， 线粒体损伤和电解质失衡会迅速杀死细胞。这意味着， 无论是基因上还是免疫上， 启动细胞因子释放和炎性细胞死亡的替代机制必须 已经进化了我们现在才开始了解这些补偿性反应及其在 塑造免疫反应。我们的初步数据，与其他初步数据的支持， PPG申请中的三个项目，将建立涉及Gasdermin 冗余和替代的蛋白酶切割事件。我们假设这些补偿机制 是细胞类型特异性的。我们进一步证实，它们影响细胞因子释放的时间和幅度， 所导致的细胞死亡的时间和炎症能力以及对炎症的体内免疫应答 刺激。本申请的总体假设是补偿焦亡损失的机制 改变对炎症损伤的炎症和免疫反应。我们进一步假设， 代偿有助于建立骨髓细胞的稳态，这些代偿性的破坏， 机制影响骨髓增生异常的病理发展和随后的白血病进展。 这项工作的长期目标是更好地了解pyroptotic代偿机制如何影响 炎症反应和免疫稳态，希望更好地了解如何操纵 这些疾病的途径。