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

基本信息

批准号：
10223156
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
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/10223156
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

项目摘要

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.

抽象的传染性细菌和炎症对生物体的毒性很大，需要立即治疗回复。其中一种称为细胞焦亡的反应会导致炎症细胞死亡，从而提醒免疫系统应对直接威胁，并确保持续的炎症作用。在古典细胞焦亡，Caspase-1 或 Caspase-11（Caspase-4/5 人）裂解成孔蛋白 Gasdermin D （GSDMD）。然后，裂解的 GSDMD 寡聚化，在细胞膜上形成孔。 Gasdermin D孔 IL-1 的形成使得 IL-1 从细胞中急剧释放，同时也破坏了细胞膜的完整性，从而线粒体损伤和电解质失衡会迅速杀死细胞。这隐含的是应该焦亡无论是通过遗传还是药理学来阻止，中和病原体对于启动细胞因子释放和炎症细胞死亡的替代机制必须保证有机体的生存已经进化了。我们现在才开始了解这些补偿反应及其在塑造免疫反应。我们的初步数据，并得到其他公司初步数据的支持本 PPG 申请中的三个项目将建立涉及 Gasdermin 的补偿机制冗余和替代蛋白酶切割事件。我们假设这些补偿机制具有细胞类型特异性。我们进一步假设它们影响细胞因子释放的时间和幅度，由此产生的细胞死亡的时间和炎症能力以及对炎症的体内免疫反应刺激。本申请的总体假设是补偿细胞焦亡损失的机制改变对炎症损伤的炎症和免疫反应。我们进一步假设这代偿有助于建立骨髓细胞稳态，并且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焦亡代偿机制如何影响炎症反应和免疫稳态，希望更好地理解如何操纵疾病中的这些途径。