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: 10441354
• 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/10441354
• 关键词: Acute; Applications Grants; Aspartate; Bacteria; Biochemical; Biochemistry; Blood Cells; CASP1 gene; CASP3 gene; Caspase; Cell Death; Cells; Cellular Membrane; Cellular biology; 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