ACTIVATED MUTANTS AS PROBES OF GM/CSF RECEPTOR FUNCTION

描述：（研究者摘要）本项目旨在研究 粒细胞-巨噬细胞集落刺激受体的功能 因子（GM-CSF）、白细胞介素-3（IL-3）和白细胞介素-5（IL-5）。 这些 因子对骨髓细胞的增殖和分化有很强的作用， 造血细胞，而且，自分泌GM-CSF的产生已经被 IL-5与一些白血病有关，而IL-5与许多过敏性疾病有关。 反应. GM-CSF、IL-3和IL-5的细胞表面受体是 并且由两个不同的亚基组成， α和β 每个因子的α亚基都是独一无二的，而β亚基则是独一无二的。 亚基（h-beta-c）由三个因子共享。 具体来说就是 建议利用一组独特的组成型活性突变体的 h-beta-c，以检查 功能性受体复合物。 这些研究将测试一个模型， 预测实际上有两种不同类型的功能性受体 复杂. （一）审查下列各项之间的联系： 细胞系中表达的受体亚基;（ii）研究分子 正常和突变形式的h-β-c关键区域的结构。 这将同时使用定向突变和核磁共振 光谱学;（iii）尝试关联不同的受体亚基 与h-β-c酪氨酸磷酸化的关系。 此外还 提出了新的试剂（例如，单克隆抗体和肽）可以 产生与h-β-c的关键区域相互作用的， 触发其信号活动。 除了提供工具来探测 受体结构，这些试剂可以提供原理证明， 这些和其它细胞因子成员的新激动剂的分离 受体家族

DESCRIPTION: (Investigator's abstract) This project aims to investigate the function of the receptors for granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-3 (IL-3) and Interleukin-5 (IL-5). These factors exert strong proliferative and differentiative effects on myeloid hemopoietic cells, and moreover, autocrine GM-CSF production has been implicated in some leukemias, while IL-5 is involved in many allergic reactions. The cell-surface receptors for GM-CSF, IL-3 and IL-5 are members of the cytokine receptor family and are comprised of two different subunits, alpha and beta. The alpha subunit is unique to each factor while the beta subunit (h-beta-c) is shared by the three factors. Specifically, it is proposed to utilize a unique set of constitutively active mutants of the h-beta-c to examine the structure, composition and activity of the functional receptor complexes. These studies will test a model which predicts that there are actually two distinct types of functional receptor complex. This will be carried out by: (i) Examining association between receptor subunits expressed in cell lines; (ii) Studying the molecular structure of a critical region of h-beta-c in both normal and mutant forms. This will use both directed mutations and nuclear magnetic resonance spectroscopy; (iii) Attempting to correlate different receptor subunit associations with tyrosine phosphorylation of h-beta-c. In addition, it is proposed that novel reagents (e.g., monoclonal antibodies and peptides) can be generated which interact with critical regions of h-beta-c and which can trigger its signalling activity. As well as providing tools to probe receptor structure, these reagents may provide a proof-of-principle for the isolation of novel agonists for these and other members of the cytokine receptor family.