ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

糖皮质激素抵抗，定义为敏感性降低状态 糖皮质激素，在许多人类疾病状态中观察到 包括癌症、哮喘、艾滋病和风湿性关节炎。 糖皮质 抵抗可能是普遍的或组织特异性的， 影响对治疗干预的反应。 糖皮质 耐药可能发生在糖皮质激素的多个步骤， 反应途径，尽管分子细节在很大程度上缺乏。 目前还没有糖皮质激素抵抗的动物模型 对可能机制的新见解。 长期目标是 该项目旨在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， 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 FKBP51的过度表达，其与 糖皮质激素受体异源复合物导致低结合亲和力。 到目前为止，没有一种亲免疫素被认为不会影响 糖皮质激素受体结合 由于FKBP51被 糖皮质激素这可能代表了一个短反馈回路，以缓和 组织在持续暴露于激素后的敏感性。 因此，在本发明中， 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， 对理解糖皮质激素的潜在广泛影响 抵抗人类疾病 本提案中概述的实验 将重点研究：（1）受体差异表达的作用 相关亲免蛋白FKBP 51和FKBP 52对 体外转录翻译糖皮质激素受体和 松鼠猴和人内源性糖皮质激素受体 （2）FKBP 51表达增加的分子基础 在松鼠猴细胞中。 这样做，我们将产生松鼠猴 细胞系、松鼠猴cDNA和基因组文库、cDNA探针，以及 松鼠猴特异性蛋白的抗体， 其他研究人员可以通过松鼠猴育种中心获得 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.