Characterization and Modulation of Caspase 4-Mediated Pyroptosis

Caspase 4 介导的焦亡的表征和调节

• 批准号: 10239081
• 负责人: Joseph Anthony Buonomo
• 金额: $ 6.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239081
• 关键词: Acylation; Affect; Affinity; Amino Acids; Biological Assay; Biological Markers; Blood Pressure; CASP1 gene; CD14 Antigen; Caspase; Caspase Inhibitor; Cell Culture Techniques; Cell Line; Cell Wall; Cells; Cessation of life; Characteristics; Chemicals; Cleaved cell; Containment; Data; Depressed mood; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disaccharides; Endotoxemia; Endotoxins; Enzyme Activation; Enzyme Inhibition; Enzymes; Epithelial; Escherichia coli; Event; Family; Family member; Genetic; Goals; Homologous Gene; Human; Immune; Immune response; Immune system; Infection; Infectious Agent; Inflammasome; Innate Immune Response; Innate Immune System; Knock-out; Knowledge; Lead; Left; Libraries; Light; Lipopolysaccharides; Malignant Neoplasms; Mediating; Medical; Molecular; Mus; N-terminal; Nature; Organ failure; Outcome; Pathology; Patients; Pattern; Peptides; Pharmacology; Phosphorylation; Plant Roots; Play; Process; Proteomics; Pseudomonas aeruginosa; Research; Role; Sepsis; Septic Shock; Serum; Shock; Signal Transduction; Site; Specificity; Stable Isotope Labeling; Stimulus; Structure; Sulfhydryl Compounds; System; TLR4 gene; Techniques; Therapeutic; Toll-like receptors; Validation; Whole Organism; Work; cell immortalization; cell type; detection assay; extracellular; immunogenic; member; mortality; novel; novel diagnostics; pathogenic bacteria; preference; pressure; receptor; response; screening; sensor; side effect; small molecule; success; therapeutic target

Project Summary/Abstract The innate immune system is the first-line of defense against both endogenous and exogenous threats, serving dual roles as both effectors and activators. However, when the innate immune system responds too robustly to a stimulus, this can lead to the host’s demise, a phenomenon we frequently call “sepsis”. Sepsis is frequently associated with infection by a gram-negative bacterial agent such as E. coli or P. aeruginosa and has been hypothesized to be driven by their immunogenic substances, with lipo-polysaccharide (LPS) likely playing a critical role in this aberrant over-signaling. This proposal outlines a plan to study the intracellular receptor of LPS, a recently discovered phenomenon seemingly the cause of endotoxemia, although the mechanisms underlying the exact nature of this receptor are still unknown. By probing both the enzyme’s activation and characterizing its downstream proteolytic events, we plan to identify if this receptor is the root cause of LPS-induced shock in human cell systems, as knockout of its murine homolog is protective against endotoxin shock when directly injected into mice. In addition to further characterizing the basic nature of this intracellular LPS receptor, we will initiate a screening campaign to identify selective molecules with a preference for this enzyme, over its closely related family members. The data generated by this proposal should identify either a validated therapeutic target for the reversal of sepsis and septic shock, a biomarker for the proper diagnosis of sepsis, or a new, highly sensitive assay for the detection of endotoxin in serum.

项目摘要/摘要 先天免疫系统是针对内源性和外源威胁的一线防御 双重作用是效果和激活剂。但是，当先天免疫系统对刺激的反应太强时， 这可能导致主持人的灭亡，这是我们经常称为“败血症”的现象。败血症经常与 革兰氏阴性细菌（例如大肠杆菌或铜绿假单胞菌）感染，已被认为是由 其免疫原性具有脂糖糖（LPS）（LPS）可能在这种异常过度信号中起关键作用。 该建议概述了研究LP的细胞内接收器的计划，最近发现的现象似乎是 尽管该受体的确切性质的基础机制仍然未知，但内毒素血症的原因。通过探测 酶的激活和表征其下游蛋白水解事件，我们计划确定该接收器是否是 人类细胞系统中LPS引起的休克的根本原因，因为其鼠同源物的敲除受到保护 直接注入小鼠时内毒素休克。除了进一步表征该细胞内的基本性质 LPS接收器，我们将启动筛选活动，以识别有选择性的分子，偏爱这种酶 它密切相关的家庭成员。该提案产生的数据应确定已验证的疗法 败血症和败血性休克逆转的靶标，适当的败血症诊断或新的，高度敏感的生物标志物 测定血清中内毒素的检测。