PLATELET ACTIVATING FACTOR SIGNALING IN LIVER

描述：血小板活化因子（PAF）是一种独特的磷脂 急性过敏和炎症反应的介质， 令人印象深刻的生物活性，包括强大的调节 对肝脏的影响。 这项建议的主要目的是提供 对PAF信号传导的分子基础有了新的认识。 费舍尔博士最近 克隆了一种新的大鼠PAF受体剪接变体（rPAF）， 结合和G蛋白偶联特性与 rPAFR。 这种受体变体，命名为rPAFRsv，通过使用较小的AT-AC产生。 先前仅在9个基因中描述了剪接机制。 拟议 Fisher博士将鉴定rPAFR和rPAFRsv 偶联并评估这两种受体在PAF信号传导中的相对作用 单独和在受体共表达范式中。 他将决定 它们独特的配体结合和G蛋白偶联的分子基础 表型为结构/功能关系提供新的见解 两种受体形式。 他将消极地评价保守派的作用， 在配体结合中细胞外受体结构域中的带电残基， 受体介导与RGS蛋白介导减毒的相对效应 在PAF刺激的信号传导中。 RGS蛋白是最近描述的家族 调节G蛋白偶联信号和PAF信号的蛋白质。 博士Fisher已经证明，这些蛋白质之一，RGS 3，参与 调节PAF信号传导。 拟议的研究将提供新的见解 研究PAF的分子作用基础， 了解PAF在肝脏和其他组织中的信号传导。

DESCRIPTION: Platelet-activating factor (PAF) is a unique phospholipid mediator of acute allergic and inflammatory reactions that displays an impressive range of biological activities including powerful regulatory effects on the liver. The major objective of this proposal is to provide new insights into the molecular basis of PAF signaling. Dr. Fisher recently cloned a novel splice variant of the rat PAF receptor (rPAF) with ligand binding and G protein-coupling characteristics distinct from that of the rPAFR. This receptor variant, named rPAFRsv, arises by use of a minor AT-AC splicing mechanism previously described in only 9 genes. In the proposed studies, Dr. Fisher will identify the G proteins to which rPAFR and rPAFRsv couple and assess the relative roles of these two receptors in PAF signaling alone and in a receptor co-expression paradigm. He will determine the molecular basis of their distinct ligand binding and G protein-coupling phenotypes to provide new insights into the structure/function relationships of both receptor forms. He will assess the role of conserved negatively charged residues in extracellular receptor domains in ligand binding and the relative effects of receptor-mediated vs. RGS protein-mediated attenuation in PAF-stimulated signaling. RGS proteins are a recently described family of proteins that regulate G protein-coupled signaling and PAF signaling. Dr. Fisher has demonstrated that one of these proteins, RGS3, is involved in regulating PAF signaling. The proposed studies will provide novel insights into the molecular basis of action of PAF and should have broad implications in understanding PAF signaling in liver and other tissues.