MOLECULAR BASIS OF DEFECTS IN GONADOTROPIN BIOSYNTHESIS

促性腺激素减退症(HH)的特点是缺乏 生产促性腺激素。促黄体生成素和促卵泡刺激素。并且可以是可逆的形式 不孕不育。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和垂体的异常反应 促性腺激素细胞。值得注意的是，对调控途径的研究 促性腺激素基因的表达现在正指向 导致生殖功能障碍的疾病。转录因子 如SF-1和DAX-1似乎在疾病的发展中起着关键作用 正常的促性腺激素表型。DAX-1的突变已被证明是 导致X连锁先天性肾上腺发育不良(AHC)和相关的HH。一个 SF-1基因敲除导致一种表型类似的疾病 老鼠模型。在这两种情况下，都有GnRH异常的证据 产生和促性腺激素反应。初步研究表明 这些转录因子调控一系列 促性腺激素特异性基因包括促性腺激素释放激素受体和 黄体生成素和卵泡刺激素的β亚基基因。这个项目的目标是执行 定义DAX-1和SF-1影响的综合系列研究 临床水平的突变。在动物模型中，以及在如何 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基因突变是促性腺激素低下的原因 人类性腺功能减退症及其临床表型 对下丘脑-垂体-性腺轴的详细研究。2)审查 SF-1和DAX-1在大鼠脑内的发育和功能关系 脑下垂体和下丘脑。SF-1和DAX-1的时空分布 表达将被确定，DAX-1基因敲除小鼠模型将被 创建的目的是评估这一功能和发展作用 动物模型中的转录因子。3)确定并描述 SF-1和DAX-1的DNA结合和功能特性 靶基因在促性腺激素细胞中表达。这些研究将提供 促性腺激素的遗传和细胞基础的新见解 虚证，将为合理治疗提供平台 干预措施。

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.