AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

描述（由申请人提供）：这是一项资源相关（R24）拨款的竞争性更新，用于研究松鼠猴作为人类糖皮质激素耐药性的动物模型。在之前的资助期内，研究人员证明松鼠猴的糖皮质激素抗性是由于糖皮质激素受体相关的一种有效形式的合作伙伴FKBP51的过度表达。这一发现揭示了这种结合fk506的亲免疫蛋白的一种新功能，它导致了一种戏剧性的生理表型，并代表了一种以前未被认识到的调节类固醇激素反应的机制。FKBP51、FKBP52和亲环蛋白40构成了大分子的亲免疫蛋白，这是一类相对较新发现的蛋白质，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。松鼠猴中FKBP51强效形式的表达提供了一个“自然实验”来设计多学科研究者感兴趣的研究。本文研究的目的是通过回答以下问题，对FKBP51进行详细的功能分析：1)松鼠猴FKBP51的哪些功能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有效抑制活性（specific Aim 1）？2)人类FKBP51和FKBP52基因是如何以组织特异性和激素/应激依赖性的方式调节的（Specific Aim 2）？3)鼠猴FKBP51在人细胞和转基因小鼠中的生化和生理作用（Specific Aim 3）？在这些研究过程中，研究人员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的组织和生物液体库（具体目标4）提供给其他研究人员。总之，这些研究将为FKBP51的生理作用提供重要的见解，同时也为南阿拉巴马大学的松鼠猴资源增加了实质性的价值。

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.