AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

糖皮质激素抵抗的动物模型

• 批准号: 6876560
• 负责人: JONATHAN G SCAMMELL
• 金额: $ 25.55万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876560
• 关键词: Saimiri; biological models; corticosteroid receptors; gel mobility shift assay; gene expression; genetic promoter element; genetic regulatory element; genetically modified animals; glucocorticoids; hormone sensitivity /resistance; human tissue; laboratory mouse; molecular shape; peptidylprolyl isomerase; phosphoprotein phosphatase; polymerase chain reaction; protein structure function; receptor binding; tissue /cell culture; transcription factor; western blottings

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.

描述（由申请人提供）：这是一项资源相关 (R24) 拨款的竞争更新，该拨款将松鼠猴作为人类糖皮质激素抵抗的动物模型进行研究。 在之前的资助期内，研究人员证明，松鼠猴的糖皮质激素耐药性是由于糖皮质激素受体相关辅伴侣 FKBP51 的有效形式过度表达所致。 这一发现揭示了这种 FK506 结合亲免素的新功能，它会产生显着的生理表型，并代表了一种以前未被认识的类固醇激素反应性调节机制。 FKBP51、FKBP52 和亲环蛋白 40 组成大分子亲免蛋白，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、心血管和神经元功能、生长发育以及癌症进展具有多种影响。 FKBP51 的有效形式在松鼠猴中的表达提供了一种“自然实验”，可以设计多学科研究人员感兴趣的研究。 本文所述研究的目标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导致其对糖皮质激素受体结合活性的有效抑制活性（具体目标 1)? 2) 人类 FKBP51 和人类 FKBP52 基因如何以组织特异性和激素/应激依赖性方式受到调节（具体目标 2）？ 3）在人类细胞和转基因小鼠中表达松鼠猴FKBP51有什么生化和生理效应（具体目标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流体库提供给其他研究人员（具体目标 4） ）。 总之，这些研究将为 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巨大的价值。