AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

描述（由申请人提供）：这是一个资源相关（R24）赠款的竞争性更新，该赠款研究松鼠猴作为人类糖皮质激素抵抗的动物模型。 在之前的研究期间，研究人员证明了松鼠猴的糖皮质激素抵抗是由糖皮质激素受体相关辅伴侣FKBP 51的有效形式的过度表达引起的。 这一发现揭示了这种FK 506结合亲免素的新功能，其导致显著的生理表型，并代表了以前未被认识到的调节类固醇激素反应性的机制。 FKBP 51、FKBP 52和亲环蛋白40组成了大分子亲免疫蛋白，这是一类相对新发现的蛋白质，其表现出广泛的分布。此外，初步研究表明这些蛋白质对内分泌、免疫、心血管和神经元功能、生长和发育以及癌症进展具有不同的影响。 在松鼠猴中表达FKBP 51的有效形式提供了一个“自然实验”，以设计多学科研究人员感兴趣的研究。 本文所述研究的目的是通过回答以下问题对FKBP 51进行详细的功能分析：1）松鼠猴FKBP 51的哪些功能结构域和特定氨基酸残基负责其对糖皮质激素受体结合活性的强效抑制活性（具体目的1）？ 2)人FKBP 51和人FKBP 52基因如何以组织特异性和激素/应激依赖性方式调节（具体目标2）？ 3)在人类细胞和转基因小鼠中表达松鼠猴FKBP 51的生物化学和生理学效应是什么（具体目标3）？在这些研究过程中，研究者将继续开发和表征与松鼠猴生物学相关的实验材料，这些材料将通过松鼠猴育种和研究资源组织和生物液体库（具体目标4）提供给其他研究者。 总之，这些研究将为FKBP 51的生理作用提供重要的见解，同时为南亚拉巴马大学的松鼠猴资源增加实质性价值。

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.