AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

描述(由申请人提供)：这是一项与资源相关的(R24)资助的竞争性续期，该资助研究松鼠猴作为人类糖皮质激素抵抗的动物模型。在之前的授权期，研究人员证明松鼠猴子的糖皮质激素抵抗是由于糖皮质激素受体相关的辅伴侣FKBP51的一种有效形式的过度表达所致。这一发现揭示了FK506结合免疫亲和素的一种新功能，它导致了一种戏剧性的生理表型，并代表了一种先前未知的调节类固醇激素反应的机制。FKBP51、FKBP52和亲环素40组成了大分子免疫亲和素，这是一类相对新发现的蛋白质，分布广泛。此外，初步研究表明，这些蛋白质对内分泌、免疫、心血管和神经功能、生长发育和癌症进展有不同的影响。在松鼠猴体内表达一种有效形式的FKBP51，为设计多学科研究人员感兴趣的研究提供了一种“自然实验”。本研究的目的是对FKBP51进行详细的功能分析，回答以下问题：1)松鼠猴FKBP51的哪些功能结构域和特定的氨基酸残基是导致其对糖皮质激素受体结合活性的有效抑制活性的原因(特定目的1)；2)人FKBP51和人FKBP52基因是如何以组织特异性和激素/应激依赖的方式调节的(特定目的2)？3)在人细胞和转基因小鼠中表达FKBP51有什么生化和生理影响(特定目的3)？在这些研究过程中，研究人员将继续开发与松鼠猴生物学有关的实验材料并确定其特征，这些材料将通过松鼠猴子育种和研究资源(特定目标4)的组织和生物流体库提供给其他研究人员。综上所述，这些研究将对FKBP51的生理作用提供重要的见解，同时为南阿拉巴马大学的松鼠猴资源增加实质性的价值。

DESCRIPTION (Provided by applicant): This is a competing renewal of a resource-related (R24) grant, which studies the squirrel monkey as an animal model of glucocorticoid resistance in humans. In the previous grant period, the investigators demonstrated that glucocorticoid resistance in squirrel monkeys results from over expression of a potent form of the glucocorticoid receptor-associated cochaperone FKBP51. This finding has uncovered a novel function of this FK506-binding immunophilin, which results in a dramatic physiological phenotype and represents a previously unrecognized mechanism by which steroid hormone responsiveness is regulated. FKBP51, FKBP52, and cyclophilin 40 make up the large molecular immunophilins, a relatively newly discovered class of proteins, which exhibit widespread distribution. Furthermore, preliminary studies indicate these proteins have diverse effects on endocrine, immune, cardiovascular and neuronal function, growth, and development, and cancer progression. The expression of a potent form of FKBP51 in squirrel monkeys offers an "experiment of nature" to design studies of interest to investigators in multiple disciplines. The goal of the studies described here is to perform a detailed functional analysis of FKBP51 by answering the following questions: 1) Which functional domains and specific amino acid residues of squirrel monkey FKBP51 are responsible for its potent inhibitory activity on glucocorticoid receptor binding activity (Specific Aim 1)? 2) How are the human FKBP51 and human FKBP52 genes regulated in a tissue-specific and hormone/stress-dependent manner (Specific Aim 2)? 3) What are the biochemical and physiological effects of expressing squirrel monkey FKBP51 in human cells and transgenic mice (Specific Aim 3)? During the course of these studies, the investigators will continue to develop and characterize experimental materials relevant to squirrel monkey biology, which will be made available to other investigators through the Tissue and Biological Fluids Bank of the Squirrel Monkey Breeding and Research Resource (Specific Aim 4). In summary, these studies will provide important insight into the physiological role of FKBP51 while at the same time adding substantial value to the Squirrel Monkey Resource at the University of South Alabama.