Identification of the molecular regulation between cell survival and cell death in response to infection induced inflammasome activation.

识别响应感染诱导的炎症小体激活的细胞存活和细胞死亡之间的分子调节。

• 批准号: 10782349
• 负责人: Gergely Imre
• 金额: $ 23.84万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10782349
• 关键词: CASP1 gene; CASP2 gene; Caspase; Cell Death; Cell Survival; Cell membrane; Communicable Diseases; Complex; Data; Endosomes; Family; Infection; Inflammasome; Inflammation; Inflammatory; Lead; Membrane; Molecular; Names; Pathogen detection; Peptide Hydrolases; Prevention approach; Proteins; Regulation; Research; Signal Transduction; Sorting; System; Testing; Toxin; Translational Research; Work; cytokine; immune activation; innovation; insight; member; novel; pathogen; protein complex; repaired; response; sensor

The molecular mechanism that defines whether inflammasome activation leads to cell death or survival and activation of immune cells, is unknown. Inflammasomes are protein complexes that function as cellular pathogen sensors. Upon sensing a pathogen, a member of the caspase cysteine protease family, caspase-1 is activated in inflammasomes. Active caspase-1 cleaves gasdermin-D (GSDMD), that subsequently forms pores throughout the plasma membrane leading to a form of cell death named pyroptosis. Paradoxically, the formation of GSDMD pores on the plasma membrane does not always lead to pyroptosis. It has been described that the endosomal sorting complex required for transport (ESCRT) results in membrane repair. It is not known what are the upstream signals which determine whether damaged membranes are repaired or not. It is an important problem, because without understanding this, the beneficial part of inflammasome activation (cytokine maturation) cannot be uncoupled from the detrimental and highly inflammatory pyroptosis. Based on our preliminary data, our hypothesis is that the ESCRT complex is inactivated via protease cleavage by caspase-2, which promotes pyroptosis. This hypothesis is supported by our preliminary work in which bacterial pore forming toxins trigger the pathogen detection response and stimulate inflammasomes. In this system, caspase-2 interacts with and cleaves the ESCRT associated protein ALIX. The rationale for the research is that, understanding this novel regulation of inflammasome driven pyroptosis could lead to new and innovative approaches to the prevention and treatment of a variety of infectious diseases. To test our central hypothesis and accomplish our overall objective, we formulated two specific aims: 1.) Elucidate the mechanism underlying the inflammasome dependent pyroptosis activation via membrane repair inhibition. Based on the preliminary data herein, our working hypothesis is that one or more regulatory components of ESCRT complex are inactivated by caspase-2 cleavage. 2.) Identify the upstream mechanisms that unleash caspase-2 dependent inactivation of membrane repair mechanisms in pyroptosis.

定义炎症体激活是否导致细胞死亡还是生存的分子机制 免疫细胞的激活尚不清楚。炎性症是蛋白质复合物的作用 细胞病原体传感器。感觉到病原体，caspase半胱氨酸蛋白酶家族的成员， caspase-1在炎症中被激活。活性caspase-1裂解Gasdermin-D（GSDMD）， 随后在整个质膜中形成毛孔，导致一种命名的细胞死亡形式 凋亡。矛盾的是，质膜上GSDMD孔的形成并不总是铅 凋亡。已经描述了运输所需的内体分选复合物（ESCRT） 导致膜修复。尚不知道什么是上游信号，决定了是否 受损的膜是否修理。这是一个重要的问题，因为不理解这一点， 炎性体激活（细胞因子成熟）的有益部分不能与 有害和高度炎症的凋亡。根据我们的初步数据，我们的假设是 通过caspase-2蛋白酶的裂解使ESCRT复合物灭活，caspase-2促进了凋亡。这 我们的初步工作支持了假设，在这种工作中，细菌形成毒素触发的孔 病原体检测反应并刺激炎症。在此系统中，caspase-2与和 切割ESCRT相关的蛋白质ALIX。研究的理由是，了解这一点 炎性体驱动的凋亡的新型调节可能会导致新的和创新的方法 预防和治疗各种传染病。测试我们的中心假设和 实现我们的整体目标，我们提出了两个具体目标：1。）阐明了基本机制 通过膜修复抑制作用的炎性体依赖性凋亡激活。基于 本文的初步数据，我们的工作假设是ESCRT的一个或多个调节组成部分 复合物被caspase-2裂解灭活。 2.）确定释放的上游机制 caspase-2依赖性膜修复机制的失活。