Gonadotropin Receptor Dimerization/Oligomerization

促性腺激素受体二聚化/寡聚化

• 批准号: 7120057
• 负责人: DEBORAH SEGALOFF
• 金额: $ 25.21万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120057
• 关键词: cell line; dimer; follicle stimulating hormone; gonadotropins; hormone receptor; luteinizing hormone; molecular assembly /self assembly; polymerization; protein protein interaction; protein sequence; protein structure function

DESCRIPTION (provided by applicant): The LH receptor (LHR) and FSH receptor (FSHR), collectively termed the gonadotropin receptors, are GPCRs that play a pivotal role in reproductive physiology. Recent studies from our laboratory and others suggest that the LHR self-associates into high molecular weight complexes consistent with dimers and oligomers of the receptor. The focus of this grant is to mechanistically and functionally examine the dimerization/oligomerization of the hLHR as well as the closely related hFSHR. In spite of the growing body of evidence that GPCRs exist as dimers/oligomers, the region(s) of a given GPCR mediating dimerization appear varied and the functional role(s) of the dimers/oligomers remains enigmatic. We propose to utilize novel and complementary approaches to address these questions as they relate to gonadotropin receptor dimerization/oligomerization. In addition, given the precedence for hetero-dimerization/oligomerization between different GPCRs, the high degree of homology between the hLHR and hFSHR, and the expression of both the hLHR and hFSHR in differentiated granulosa cells, a particularly relevant question we will also address is whether the hLHR and hFSHR form hetero-dimers/oligomers and what the functional ramifications of this are. The specific aims of the grant, therefore, are to: (1) determine the functional role(s) of cell surface gonadotropin receptor dimerization; (2) determine if the hLHR and hFSHR hetero-dimerize and, if so, examine the functional consequences of this phenomenon; and (3) determine the structural region(s) mediating homo- and hetero-dimerization of the gonadotropin receptors. Overall, the proposed studies in the grant will contribute novel and significant insights into homo- and heterodimerization/oligomerization of the gonadotropin receptors, providing new paradigms for the roles of these receptors in reproductive endocrinology.

描述（由申请人提供）：LH受体（LHR）和FSH受体（FSHR）统称为促性腺激素受体，是在生殖生理中起关键作用的gpcr。我们实验室和其他人最近的研究表明，LHR自结合成高分子量的复合物，与受体的二聚体和低聚物一致。这项资助的重点是对hLHR及其密切相关的hFSHR的二聚化/寡聚化进行机制和功能研究。尽管越来越多的证据表明GPCR作为二聚体/低聚体存在，但给定GPCR介导二聚体的区域似乎各不相同，二聚体/低聚体的功能作用仍然是谜。我们建议利用新的和互补的方法来解决这些问题，因为它们与促性腺激素受体二聚化/寡聚化有关。此外，考虑到不同gpcr之间异二聚/寡聚的优先性，hLHR和hFSHR之间的高度同源性，以及hLHR和hFSHR在分化的颗粒细胞中的表达，我们还将解决一个特别相关的问题，即hLHR和hFSHR是否形成异二聚体/寡聚物，以及这一现象的功能分支是什么。因此，该基金的具体目的是：(1)确定细胞表面促性腺激素受体二聚化的功能作用；(2)确定hLHR和hFSHR是否异二聚化，如果异二聚化，检查这种现象的功能后果；(3)确定介导促性腺激素受体同源和异二聚化的结构区域。总的来说，本基金提出的研究将对促性腺激素受体的同源和异源二聚化/寡聚化提供新颖和重要的见解，为这些受体在生殖内分泌学中的作用提供新的范式。