IN VIVO FUNCTION OF INTERLEUKIN 1 RECEPTOR ANTAGONIST

描述(改编自调查者摘要)：本提案旨在 了解内源性表达的白介素1的体内功能 受体拮抗剂(IL-1ra)。缺乏IL-1ra(基因敲除)的小鼠和小鼠 过度表达IL-1ra(转基因)将被描述。这些突变体 小鼠与野生型产仔对照。拟议中的实验将进一步 分析潜在的细胞和分子生理反应 不同水平的IL-1ra在这些小鼠中的表达。中的更改 将分析细胞因子谱，以及白细胞增殖和 迁移。这些研究将提供对体内的更深层次的了解 对IL-1ra作出反应并提供明确表型的机制 在一系列上位性实验中用作遗传标记。双倍与 将构建涉及IL-1ra基因敲除和 过度表达、IL-1受体缺失、IL-1βTa 114基因敲除和 Caspase-1(ICE)基因敲除，以定义 IL-1/IL-1ra途径的成员。这些上位论实验 旨在确定哪些表型是由于细胞内与 IL-1ra的分泌形式，以及是否存在另一个靶点 除IL-1受体外，对于IL-1ra，其表型 单一突变体目前强烈建议。

DESCRIPTION (Adapted from Investigator's abstract): This proposal seeks to understand the in vivo functions of endogenously expressed interleukin-1 receptor antagonist (IL-1ra). Mice lacking IL-1ra (gene knockouts) and mice over expressing IL-1ra (transgenics) will be characterized. These mutant mice to wildtype littermate controls. The proposed experiments will further analyze the underlying cellular and molecular physiological responses to the different levels of IL-1ra expression that occur in these mice. Changes in cytokine profiles will be analyzed as will leukocyte proliferation and migration. These studies will provide a deeper understanding of the in vivo mechanisms that respond to IL-1ra and provide clear phenotypes that can be used as genetic markers in a set of epistasis experiments. Double and triple mutants will be constructed involving the IL-1ra knockouts and overexpressors, IL-1 receptor nulls, IL-1beta TAbetas114 knockouts and caspase-1 (ICE) knockouts, in order to define the interactions between members of the IL-1/IL-1ra pathway. These epistasis experiments are intended to determine which phenotypes are due to the intracellular versus the secreted forms of IL-1ra, and to resolve whether another target exists for IL-1ra in addition to the IL-1 receptor, which the phenotypes of the single mutants currently strongly suggest.