PROJECT 1 - INTEGRATION OF HORMONE SIGNALING IN THE PITUITARY GONADOTROPE

控制垂体促性腺激素产生的激素影响的精确相互作用 包括激活素和卵泡抑素的内分泌、旁分泌和自分泌作用，下丘脑促性腺激素， 促性腺激素释放激素（GnRH）和性腺类固醇激素。我们的重点将是细胞和分子 激活素、GnRH和类固醇激素调节垂体促性腺激素的机制：促黄体生成 激素（LH）和卵泡刺激素（FSH），使用体外培养的细胞，以及它们在 生理学和病理生理学，在体内，在小鼠中使用靶向基因缺失。在目标1中，我们将重点关注 激活素对促性腺激素基因的调节，其与GnRH的相互作用，以及促性腺激素的生理作用 激活素信号在促性腺细胞，在体内，在靶向Smad缺陷小鼠。在目标2中，我们讨论了 孕激素和雄激素在促性腺激素基因的负性和正性调节中的作用及其 与激活素信号传导的相互作用。此外，我们将利用孕酮的靶向破坏， 雄激素受体基因，在体内，以评估其在垂体和脑内的作用，在正常女性 生殖功能临床和动物研究都强调了青春期提前的产前起源 和多囊卵巢综合征，共同点是子宫内雄激素异常暴露。我们 将使用高脂肪喂养和子宫内暴露于雄激素的模型来研究这一假设， 通过雄激素受体起作用的雄激素是青春期提前和 多囊卵巢综合症的症状有哪些我们的总体目标是了解 激活素、GnRH和类固醇激素在正常人促性腺激素中调节LH和FSH的作用 和病理生理状态。因此，肽类激素、生长因子、类固醇、受体， 下丘脑释放因子直接或间接控制促性腺激素的合成， 使用分子，细胞，遗传和小鼠技术的设备进行研究，目标是 发展一个详细的了解分子机制介导正常和无序 女性生殖功能

The precise interplay of hormonal influences that governs gonadotropin hormone production by the pituitary ncludes endocrine, paracrine and autocrine actions of activin and follistatin, hypothalamic gonadotropin- ¿eleasing hormone (GnRH), and gonadal steroid hormones. Our focus will be the cellular and molecular mechanisms of activin, GnRH, and steroid hormone regulation of the pituitary gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH), using cultured cells in vitro, and their roles in physiology and pathophysiology, in vivo, using targeted gene deletion in mice. In Aim 1, we will focus on the regulation of the gonadotropin genes by activin, its interactions with GnRH, and the physiological role of activin signaling in the gonadotrope, in vivo, in targeted Smad-deficient mice. In Aim 2, we address the roles of progestins and androgens in both negative and positive regulation of the gonadotropin genes and their nteractions with activin signaling. Further, we will utilize targeted disruption of the progesterone and androgen receptor genes, in vivo, to assess their role within the pituitary and brain, in normal female reproductive function. Both clinical and animal studies underscore the prenatal origin of premature puberty and polycystic ovary syndrome with the common thread being abnormal androgen exposure in utero. We will use models of high-fat feeding and in utero exposure to androgens to invesigate the hypothesis that androgens, acting through the androgen receptor, are causative for advancement of puberty and for development of the hallmarks of polycystic ovary syndrome. Our overall goal is to understand the integration of activin, GnRH, and steroid hormone action in the regulation of LH and FSH in the gonadotrope in normal and pathopysiological states. Thus, the interplay of peptide hormones, growth factors, steroids, receptors, and hypothalamic releasing factors directly and indirectly controlling gonadotropin synthesis will be investigated using the armamentarium of molecular, cellular, genetic, and mouse technologies with the goal of developing a detailed understanding of the molecular mechanisms mediating normal and disordered female reproductive function.