ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

糖皮质激素抵抗，定义为敏感性减弱状态 对糖皮质激素的作用，在许多人类疾病状态下观察到 包括癌症、哮喘、艾滋病和类风湿性关节炎。糖皮质激素 耐药性可能是全面性的或组织特异性的，并可能对 影响对治疗干预的反应。糖皮质激素 耐药可能发生在糖皮质激素的多个步骤中 反应途径，尽管在很大程度上缺乏分子细节。 目前还没有糖皮质激素抵抗Gain的动物模型。 对可能的机制有了新的见解。这样做的长期目标是 项目是了解糖皮质激素的分子基础 松鼠猴是一种新热带灵长类动物，具有天然的 发生糖皮质激素抵抗。我们假设糖皮质激素 松鼠猴的抵抗力来自于亲缘关系 免疫亲和素FKBP51的过表达 糖皮质激素受体异源复合体导致结合亲和力低。 到目前为止，没有一种免疫亲和素被认为不会影响 糖皮质激素受体结合。由于FKBP51被上调 糖皮质激素这可能代表了一个短暂的反馈循环，以调节 组织对持续接触荷尔蒙的敏感性。因此， 我们对松鼠猴的初步研究发现了一种新的 调节糖皮质激素敏感性的机制，一项与 对糖皮质激素的理解具有潜在的广泛意义 人类疾病中的抵抗力。这项提案中概述的实验 将重点放在：(1)受体差异表达的作用 联合免疫亲和素FKBP51和FKBP52对亲和力的影响 体外转录的糖皮质激素受体及其受体 松鼠、猴和人的内源性糖皮质激素受体 淋巴细胞；(2)FKBP51表达增加的分子基础 在松鼠猴的细胞里。在这样做的过程中，我们将产生松鼠猴子 细胞系、松鼠猴cDNA库和基因组文库、cDNA探针和 针对松鼠猴子特异性蛋白的抗体将被制造出来 可供其他调查人员通过饲养松鼠猴子获得 和研究资源。

Glucocorticoid resistance, defined as a diminished state of sensitivity to glucocorticoids, is observed in a number of human disease states including cancer, asthma, AIDS and rheumatoid arthritis. Glucocorticoid resistance may be generalized or tissue-specific and may profoundly influence response to therapeutic intervention. Glucocorticoid resistance likely occurs at multiple steps in the glucocorticoid response pathway although the molecular details are largely lacking. There have been no animal models of glucocorticoid resistance to gain new insight into possible mechanisms. The long-term goal of this project is to understand the molecular basis for glucocorticoid sensitivity in the squirrel monkey, a neotropical primate with naturally occurring glucocorticoid resistance. We hypothesize that glucocorticoid resistance in the squirrel monkey results from the relative overexpression of the immunophilin FKBP51 which associates with the glucocorticoid receptor heterocomplex leading to low binding affinity. Until now, none of the immunophilins had not been thought to influence glucocorticoid receptor binding. As FKBP51 is upregulated by glucocorticoids this may represent a short-feedback loop to moderate the sensitivity of a tissue upon continued exposure to the hormone. Thus, our preliminary studies in the squirrel monkey have uncovered a novel mechanism for regulating glucocorticoid sensitivity, a finding with potentially broad implications to understanding glucocorticoid resistance in human disease. The experiments outlined in this proposal will focus on: (1) the role of differential expression of the receptor associated-immunophilins FKBP51 and FKBP52 on the binding affinity of in vitro transcribed-translated glucocorticoid receptor and of endogenous glucocorticoid receptors in squirrel monkey and human lymphocytes; (2) the molecular basis for increased expression of FKBP51 in squirrel monkey cells. In so doing, we will generate squirrel monkey cell lines, squirrel monkey cDNA and genomic libraries, cDNA probes, and antibodies to squirrel monkey-specific proteins which will be made available to other investigators through the Squirrel Monkey Breeding and Research Resource.