PLATELET ACTIVATING FACTOR SIGNALING IN LIVER

说明：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中介物，表现为 令人印象深刻的一系列生物活动，包括强大的监管 对肝脏的影响。这项提案的主要目标是提供 对PAF信号的分子基础的新见解。费舍尔博士最近 大鼠纤溶酶原激活剂受体(RPAF)新的配体剪接变异体的克隆 结合和G蛋白偶联特性不同于 RPAFR。这种称为rPAFRsv的受体变体是通过使用一个小的AT-AC产生的 先前仅在9个基因中描述了剪接机制。在建议的 研究表明，Fisher博士将确定rPAFR和rPAFRsv与G蛋白的结合 偶联和评估这两种受体在PAF信号中的相对作用 单独和在受体共表达范例中。他将决定 它们不同配体结合和G蛋白偶联的分子基础 提供对结构/功能关系的新见解的表型 两种受体形式。他将对保守党的作用进行负面评估 配基结合中胞外受体区的带电残基 受体介导的相对效应与RGS蛋白介导的衰减 在PAF刺激的信号转导中。Rgs蛋白是最近被描述的一个家族。 调节G蛋白偶联信号和PAF信号的蛋白质。 费舍尔博士已经证明，其中一种蛋白质RGS3参与了 调节PAF信号。拟议的研究将提供新的见解 探讨PAF作用的分子基础，应该具有广泛的意义 了解肝脏和其他组织中的PAF信号。

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.