INTERACTIONS OF ANDROGEN RECEPTOR POLYGLUTAMINE TRACT

雄激素受体多聚谷氨酰胺束的相互作用

• 批准号: 6151589
• 负责人: DIANE E MERRY
• 金额: $ 10.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151589
• 关键词: androgen receptor; bacteriophage lambda; binding proteins; brain; chemical chain length; cytotoxicity; degenerative motor system disease; genetic library; genetically modified animals; glutamine; intermolecular interaction; molecular site; neurogenetics; neuromuscular disorder; neurons; nucleic acid repetitive sequence; protein sequence; protein structure function; receptor binding; tissue /cell culture; yeast two hybrid system

DESCRIPTION: (Applicant's abstract) Spinal and bulbar muscular atrophy is an adult-onset neurodegenerative disease characterized by muscle weakness, atrophy, and fasciculations. It is a member of a growing family of neurodegenerative diseases caused by the expansion of a CAG repeat that encodes a poly-glutamine tract within the associated protein coding sequence. Our hypothesis is that the neurodegeneration seen in these diseases results from the gain of a toxic function in the encoded protein due to the presence of the poly-glutamine tract, and that this toxic effect is mediated by specific protein-protein interactions. This project proposes to identify and isolate proteins (and their associated cDNAs) that interact with androgen receptor containing different length poly-glutamine tracts. This will be done in two ways. First, we will use a yeast two-hybrid system to identify proteins that interact with the amino terminal region of the androgen receptor containing 24, 45, or 66 glutamine repeats. We will also use this system to characterize the dependence of interactions on the length of the poly-glutamine tract. We expect that for an interaction to play a role in the pathogenic process, it should be affected in some way by the length of the glutamine repeat. Second, we will screen a lambda phage expression library using radioactively-labeled androgen receptor proteins of different repeat lengths purified from bacteria. This method will allow us to differentially screen libraries using full-length androgen receptor containing different length poly-glutamine tracts. This system will also be exploited for characterization of binding properties of proteins identified through either approach. Lastly, we will characterize the physiologic relevance of protein interactions identified through these screens using cell culture and transgenic model systems that we have developed. The results of these experiments should provide insights into the molecular mechanism by which expanded poly-glutamine tracts become toxic to neurons, and may consequently provide targets for therapeutic intervention. In addition, understanding androgen receptor protein interactions in neurons will increase our understanding of the role of steroid hormone receptors in these cells.

描述：（申请人摘要）脊髓和球性肌肉萎缩是