MOLECULAR BASIS OF DEFECTS IN GONADOTROPIN BIOSYNTHESIS

促性腺激素生物合成缺陷的分子基础

• 批准号: 6583743
• 负责人: James Larry JAMESON
• 金额: $ 23.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583743
• 关键词: clinical research; family genetics; follicle stimulating hormone; gene expression; gene mutation; gene targeting; genetic transcription; hormone regulation /control mechanism; human subject; hypogonadism; hypothalamic pituitary axis; laboratory mouse; luteinizing hormone; molecular pathology; peptide hormone biosynthesis; pituitary gonadal axis; secretion; tissue /cell culture; transcription factor

Hypogonadotropic hypogonadism (HH) is characterized by deficiency in the production of the gonadotropins. LH and FSH. and can be a reversible form of infertility. Causes of HH include deficient production or regulation of hypothalamic GnRH as well as abnormal responsiveness of the pituitary gonadotrope cell. Remarkably, studies of pathways that regulate expression of the gonadotropin genes are now pointing the way towards disorders that underlie reproductive dysfunction. Transcription factors such as SF-1 and DAX-1 appear to play a key role in the development of the normal gonadotrope phenotype. Mutations in DAX-1 have been shown to cause X-linked adrenal hypoplasia congenita (AHC) and associated HH. A gene knockout of SF-1 results in a phenotypically similar disorder in a mouse model. In both cases, there is evidence for abnormalities in GnRH production and gonadotrope responsiveness. Preliminary studies suggest that these transcription factors regulate the expression of an array of gonadotrope-specific genes including the GnRH receptor and the alpha and beta-subunit genes for LH and FSH. The goal of this project is to perform an integrated series of studies that define the effects of DAX-1 and SF-1 mutations at a clinical level. in animal models, and in terms of how these proteins function at a cellular level. The specific aims are to: 1) Identify DAX-1 and SF-1 gene mutations as causes of hypogonadotropic hypogonadism in humans and to characterize the clinical phenotypes using detailed studies of the hypothalamic-pituitary-gonadal axis. 2) Examine the developmental and functional relationships of SF-1 and DAX-1 in the pituitary and hypothalamus. The spaciotemporal patterns of SF-1 and DAX-1 expression will be determined and a DAX-1 knockout mouse model will be created to evaluate the functional and developmental role of this transcription factor in an animal model. 3) Identify and characterize the DNA-binding and functional properties of SF-1 and DAX-1 with respect to target genes expressed in gonadotrope cells. These studies will provide new insights into the genetic and cellular basis of gonadotropin deficiency syndromes and will provide a platform for rational therapeutic interventions.

低促性腺激素性性腺功能减退症（HH）的特征是 促性腺激素的产生。LH和FSH。并且可以是可逆形式 不孕症的症状HH的原因包括生产或监管不足 下丘脑促性腺激素释放激素以及垂体的异常反应 促性腺细胞值得注意的是，关于调节 促性腺激素基因的表达现在指向了 导致生殖功能障碍的疾病转录因子 如SF-1和DAX-1似乎在发展中发挥了关键作用， 正常的促性腺细胞表型。DAX-1的突变已被证明 导致X连锁先天性肾上腺发育不全（AHC）和相关HH。一 SF-1基因敲除导致表型相似的疾病， 小鼠模型在这两种情况下，有证据表明GnRH异常 生产和促性腺激素反应。初步研究表明 这些转录因子调控着一系列 促性腺激素特异性基因，包括GnRH受体和α和 LH和FSH的β亚基基因。该项目的目标是执行 一系列综合研究，确定DAX-1和SF-1的作用 在临床水平上的突变。在动物模型中， 这些蛋白质在细胞水平上起作用。具体目标是： 1)确定DAX-1和SF-1基因突变是低促性腺激素的原因 人类性腺功能减退症，并使用 下丘脑-垂体-性腺轴的详细研究。2)审查 SF-1和DAX-1的发育和功能关系， 垂体和下丘脑。SF-1和DAX-1的时空分布 将确定DAX-1表达，并将建立DAX-1敲除小鼠模型。 建立评估的功能和发展的作用， 在动物模型中的转录因子。3)识别和表征 SF-1和DAX-1的DNA结合和功能特性， 促性腺细胞中表达的靶基因。这些研究将提供 对促性腺激素的遗传和细胞基础的新认识 为中医辨证论治提供了一个平台 干预措施。