IN VIVO FUNCTION OF INTERLEUKIN 1 RECEPTOR ANTAGONIST

描述（改编自研究者摘要）：本提案旨在 了解内源性表达的白细胞介素-1的体内功能 受体拮抗剂（IL-1 ra）。 缺乏IL-1 ra的小鼠（基因敲除）和 将表征过表达IL-1 ra（转基因）。 这些突变 小鼠与野生型同窝对照。 拟议的实验将进一步 分析潜在的细胞和分子生理反应， 不同水平的IL-1 ra表达。 变化 将分析细胞因子谱以及白细胞增殖， 迁移 这些研究将提供对体内 对IL-1 ra有反应的机制，并提供明确的表型， 在上位性实验中用作遗传标记。 双和 将构建涉及IL-1 ra敲除的三重突变体， 过表达、IL-1受体无效、IL-1 β TA β 114敲除和 caspase-1（ICE）敲除，以确定 IL-1/IL-1 ra通路的成员。 这些上位性实验是 旨在确定哪些表型是由于细胞内与 IL-1 ra的分泌形式，并确定是否存在另一个靶标 对于IL-1 ra，除了IL-1受体， 单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.