Cellular Engineering to identify gasdermin protein networks regulating inflammatory cell death

摘要 感染性细菌和炎症性侮辱对有机体的毒性很大，需要立即 回应。一种这样的反应，称为下垂，会导致炎症细胞死亡，这两种反应都会提醒 免疫系统受到直接威胁，也确保了持续的炎症努力。在古典中 热下垂，Caspase-1或Caspase-11(Caspase-4/5人)裂解孔形成蛋白Gasdermin D (GSDMD)。这种裂解的GSDMD然后寡聚，在细胞膜上形成一个孔。Gasdermin D孔 形成允许IL-1从细胞中急剧释放，同时也破坏了膜的完整性，从而 线粒体损伤和电解质失衡会迅速杀死细胞。这其中隐含的意思是，如果上睑下垂 无论是从遗传上还是从药物上讲，病原体的中和对 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反应及其在 塑造免疫反应。我们的初步数据，以及来自另一家的初步数据的支持 PPG应用程序中的三个项目将建立涉及Gasdermin的补偿机制 冗余性和替代的蛋白酶裂解事件。我们假设这些补偿机制 是特定细胞类型的。我们进一步假设，它们影响细胞因子释放的时间和幅度，即 导致细胞死亡的时间和炎症能力以及体内对炎症的免疫反应 刺激物。这项应用的总体假设是，补偿上睑下垂丧失的机制 改变对炎症性侮辱的炎症和免疫反应。我们进一步假设这一点 补偿有助于建立髓系细胞动态平衡，而这些代偿性破坏 机制影响骨髓发育不良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毒症的代偿机制如何影响 炎症反应和免疫动态平衡，希望更好地理解如何操作 疾病中的这些途径。

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.