Generation of IL-33 Deficient Mice

描述(由申请人提供)：该项目的目标是产生IL-33缺陷小鼠，并对它们进行初步鉴定。IL-33是新近发现的IL-1家族成员，包括IL-1-α、IL-1-β和IL-18。2005年11月，IL-33被确定为白介素1受体家族成员ST2的胞外配体(正式名称为IL1RL1)。有关IL-33的研究文献迅速增多，表明作为ST2受体的胞外配体，IL-33在变态反应和免疫性疾病中具有强大的免疫调节功能。IL-33与2003年发现的一种被称为高内皮微静脉核因子(NF-HEV)的分子完全相同，后者是一种在内皮细胞中高表达的核因子，具有转录抑制特性。内源性核IL-33在血管内皮细胞和上皮细胞中表达，代表了慢性炎症中IL-33调节的一种添加方式。在IL-33被确定为ST2受体的配体之前，ST2受体已经在临床和实验研究中与炎症性哮喘、肺纤维化、血管疾病、脓毒症和心脏病有关。虽然目前已经有了ST2受体基因敲除小鼠，但它不能解决IL-33在骨髓前体细胞出口和扩增中的作用，对IL-33/ST2L信号的调节，以及IL-33在慢性炎症调节中的核功能。基于ST2受体基因敲除小鼠的生存能力，我们预计IL-33基因敲除小鼠将是存活的。目前尚不能获得的IL-33基因敲除小鼠，具有在人类慢性炎症性疾病中识别新的调节机制的高潜力。 公共卫生相关性：项目简介该项目的目标是产生IL-33缺陷小鼠。IL-33是白介素1家族的成员之一，最近被确定为白介素1受体家族成员ST2的胞外配体。有关IL-33的研究文献迅速增多，表明作为ST2受体的胞外配体，IL-33在变态反应和免疫性疾病中具有强大的免疫调节功能。目前尚不能获得的IL-33基因敲除小鼠，具有在人类肺部和慢性炎症性疾病中识别新的调节机制的高潜力。

DESCRIPTION (provided by applicant): The objective of this project is to generate IL-33 deficient mice and to subject them to initial characterization. IL-33 is a recently identified member of the interleukin-1 family, which includes IL-1- alpha, IL-1-beta and IL-18. In November 2005, IL-33 was identified as the extracellular ligand for an interleukin-1 receptor family member, ST2 (official name IL1RL1). The rapidly expanding literature on IL- 33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. IL-33 is identical to a molecule discovered in 2003 called Nuclear Factor of High Endothelial Venules (NF-HEV), a nuclear factor highly expressed in the endothelium with transcriptional repressor properties. Endogenous nuclear IL-33 is expressed in endothelial and epithelial cells representing an addition mode of IL-33 regulation in chronic inflammation. Prior to the identification of IL-33 as the ligand for the ST2 receptor, the ST2 receptor had been associated with inflammatory asthma, pulmonary fibrosis, vascular diseases, sepsis and heart disease in clinical and experimental studies. While an ST2 receptor knockout mouse is currently available, it cannot address the roles of IL-33 in bone marrow progenitor cell egress and expansion, regulation of IL-33/ST2L signaling, and nuclear functions of IL-33 in the regulation of chronic inflammation. Based on the viability of ST2 receptor knockout mice, we anticipate that IL-33 knockout mice will be viable. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The objective of this project is to generate IL-33 deficient mice. IL-33 is a member of the interleukin-1 family that was recently identified as the extracellular ligand for an interleukin-1 receptor family member, ST2. The rapidly expanding literature on IL-33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human pulmonary and chronic inflammatory diseases.