PROJECT 1 - INTEGRATION OF HORMONE SIGNALING IN THE PITUITARY GONADOTROPE

调节脑下垂体促性腺激素分泌的激素影响的精确相互作用 包括激活素、卵泡抑素、下丘脑促性腺激素的内分泌、旁分泌和自分泌作用。 促性腺激素释放激素(GnRH)和性腺类固醇激素。我们的重点将放在细胞和分子上 激活素、促性腺激素释放激素和类固醇激素调节垂体促性腺激素的机制：黄体化 激素(LH)和卵泡刺激素(FSH)在体外培养细胞中的作用 生理学和病理生理学，在体内，使用小鼠的靶向基因缺失。在目标1中，我们将重点介绍 激活素对促性腺激素基因的调节、与促性腺激素释放激素的相互作用以及促性腺激素释放激素的生理作用 体内靶向Smad基因缺陷小鼠促性腺激素中的激活素信号。在目标2中，我们解决了这些角色 孕激素和雄激素对促性腺激素基因的负向和正向调节及其相互作用 与激活素信号的相互作用。此外，我们将利用靶向干扰黄体酮和 体内雄激素受体基因，以评估它们在正常女性脑下垂体和大脑中的作用 生殖功能。临床和动物研究都强调了早熟的胎儿期起源 以宫内雄激素异常暴露为主线的多囊卵巢综合征。我们 将使用高脂肪喂养和宫内雄激素暴露的模型来研究这一假设 雄激素通过雄激素受体发挥作用，导致青春期提前和 多囊卵巢综合征征象的发展。我们的总体目标是了解集成 激活素、促性腺激素释放激素和类固醇激素对正常人促性腺激素中促黄体生成素和卵泡刺激素的调节作用 以及病理生理状态。因此，多肽激素、生长因子、类固醇、受体、 而下丘脑释放因子直接和间接控制促性腺激素的合成 利用分子技术、细胞技术、遗传技术和小鼠技术进行研究，目的是 对调节正常和无序的分子机制有了详细的了解 女性的生殖功能。

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.