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REGULATION OF GLUCOCORTICOID RECEPTOR FUNCTION BY CAMP

CAMP 对糖皮质激素受体功能的调节

基本信息

批准号：
3237350
负责人：
DONALD J GRUOL
金额：
$ 14.19万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-01-01 至 1991-03-31
项目状态：
已结题

项目摘要

The overall goal is to achieve a greater understanding of the mechanisms by which glucocorticoid hormones and hormones which act through cAMP regulate lymphoid viability and growth. Both steroids and cyclic nucleotide have the demonstrated capacity to suppress the immune system as a part of an organism's response to stress. The primary transducers for these agents are known to be a gene- regulating receptor and a protein kinase, but the immediate functions that they affect are only partially understood. Evidence of crossregulation is presented, showing that cAMP has the ability to promote an increase of glucocorticoid binding capacity in a murine lymphoma line, WEHI-7. Two possible mechanisms are proposed: 1) Conversion of a cryptic pool of receptors into an active form; 2) Increased synthesis of receptor protein. The involvement of receptor modification vs. synthesis will be studied using 2D-gel electrophoresis, thioredoxin assays, density gradient analysis and molecular probes for synthesis of receptor protein and messenger RNA. At certain stages of T-cell differentiation, glucocorticoids and cyclic nucleotide can elicit a cytolytic response. This behavior has provided a basis for the use of steroids in treatment of certain forms of leukemia. The cytolytic response has also presented a tool for selection of resistant variants containing altered glucocorticoid receptors and cyclic AMP-dependent protein kinase. This proposal deals with the discovery and characterization of a "second generation" of steroid/cyclic nucleotide resistant variants. It was found that ac initial selection for resistance to cAMP in the murine lymphoma WEHI-7 acts as a permissive step towards selection of steroid resistance at s high frequency. The results indicate that the variants which have been obtained represent new forms of steroid resistance, possibly involving functions that activate the glucocorticoid receptor into a steroid binding state. Characterization of these variant cell lines is proposed in an attempt to identify the altered functions which lead to the loss of functional receptor.

总体目标是加深对糖皮质激素及其作用机制通过 cAMP 调节淋巴活力和生长。两种类固醇和环核苷酸具有抑制的能力免疫系统是有机体对压力做出反应的一部分。已知这些药物的主要传感器是基因调节受体和蛋白激酶，但直接它们所影响的功能仅被部分了解。证据提出了交叉调节，表明 cAMP 具有促进糖皮质激素结合能力的增加鼠淋巴瘤系，WEHI-7。两种可能的机制是建议：1）将一个神秘的受体池转化为一个主动形式； 2) 受体蛋白的合成增加。这将研究受体修饰与合成的参与使用 2D 凝胶电泳、硫氧还蛋白测定、密度梯度受体蛋白合成的分析和分子探针信使RNA。在 T 细胞分化的某些阶段，糖皮质激素和环核苷酸可引发溶细胞反应。这种行为为类固醇的治疗提供了基础某些形式的白血病。细胞溶解反应也提出了一种选择耐药变体的工具，其中包含改变糖皮质激素受体和环AMP依赖性蛋白激酶。该提案涉及发现和 “第二代”类固醇/环状化合物的表征核苷酸抗性变体。发现ac初始小鼠淋巴瘤 WEHI-7 中 cAMP 抗性的选择作为选择类固醇抗性的允许步骤高频。结果表明，具有所获得的代表类固醇抗性的新形式，可能涉及激活糖皮质激素受体的功能类固醇结合状态。这些变异细胞的表征提出线路是为了尝试识别改变的功能从而导致功能性受体的丧失。