AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

糖皮质激素抵抗的动物模型

基本信息

批准号：
7217244
负责人：
JONATHAN G SCAMMELL
金额：
$ 24.23万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7217244
关键词：
Adrenal hormone preparation Affinity Alabama Amino Acids Animal Model Antibodies Base Sequence Binding Biochemical Biological Biology Biomedical Research Breeding Cardiovascular system Cell Line Cells Cercopithecidae Class Complement Complementary DNA Discipline Endocrine Exhibits Experimental Models FK506 binding protein 5 Genes Genomics Glucocorticoid Receptor Glucocorticoids Goals Grant Growth and Development function Hormones Human Hydrocortisone Immune Immunophilins Knowledge Liquid substance Molecular Molecular Chaperones Molecular Weight Monoclonal Antibody R24 Nature Neurons Numbers Peptidylprolyl Isomerase Phenotype Physiological Play Primates Protein Tyrosine Kinase Proteins Reagent Regulation Research Design Research Personnel Resistance Resources Role Saimiri Stress Structure T-Lymphocyte Time Tissues Transgenic Mice Universities Work cyclophilin D cytokine human disease insight interest member novel protein function receptor binding research study steroid hormone steroid hormone receptor tacrolimus binding protein 4 trait tumor progression

项目摘要

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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular cloning of pituitary glycoprotein alpha-subunit and follicle stimulating hormone and chorionic gonadotropin beta-subunits from New World squirrel monkey and owl monkey.

新大陆松鼠猴和鸮猴的垂体糖蛋白α亚基、促卵泡激素和绒毛膜促性腺激素β亚基的分子克隆。

DOI：
10.1016/j.ygcen.2007.08.004
发表时间：
2008
期刊：
General and comparative endocrinology
影响因子：
2.7
作者：
Scammell,JonathanG;Funkhouser,JaneD;Moyer,FelriciaS;Gibson,SusanV;Willis,DonnaL
通讯作者：
Willis,DonnaL

Tissue-specific expression of squirrel monkey chorionic gonadotropin.

松鼠猴绒毛膜促性腺激素的组织特异性表达。

DOI：
10.1016/j.ygcen.2010.11.023
发表时间：
2011
期刊：
General and comparative endocrinology
影响因子：
2.7
作者：
Vasauskas,AudreyA;Hubler,TinaR;Boston,Lori;Scammell,JonathanG
通讯作者：
Scammell,JonathanG

Organization and function of the FKBP52 and FKBP51 genes.

DOI：
10.1016/j.coph.2011.03.013
发表时间：
2011-08
期刊：
CURRENT OPINION IN PHARMACOLOGY
影响因子：
4
作者：
Cioffi, Donna L.;Hubler, Tina R.;Scammell, Jonathan G.
通讯作者：
Scammell, Jonathan G.

The origin of four squirrel monkey cell lines established by karyotype analysis.

通过核型分析建立的四种松鼠猴细胞系的起源。

DOI：
10.1159/000056995
发表时间：
2001
期刊：
Cytogenetics and cell genetics
影响因子：
0
作者：
Scammell,JG;Wright,JL;Tuck-Muller,CM
通讯作者：
Tuck-Muller,CM

Regulation and distribution of squirrel monkey chorionic gonadotropin and secretogranin II in the pituitary.

松鼠猴绒毛膜促性腺激素和促分泌素II在垂体中的调节和分布。

DOI：
10.1016/j.ygcen.2010.11.010
发表时间：
2011
期刊：
General and comparative endocrinology
影响因子：
2.7
作者：
Vasauskas,AudreyA;Hubler,TinaR;Mahanic,Christina;Gibson,Susan;Kahn,AndreaG;Scammell,JonathanG
通讯作者：
Scammell,JonathanG