The precise interplay of hormonal influences that governs gonadotropin hormone production by the pituitary includes endocrine, paracrine and autocrine actions of activin and follistatin, hypothalamic gonadotropin-releasing 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 interactions 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.
Both clinical studies and animal models indicate a prenatal origin for precocious puberty and polycystic ovary syndrome. These disorders share the common thread of hyperandrogenemia or androgen exposure in utero. In addition, the contribution of androgen receptors in the neuroendocrine system to normal female puberty and estrous cycles is not well understood. The studies herein will address the normal and pathophysiological actions of androgens in the female pituitary and brain to gain insight into the role of androgens in women.
|Sen, Supriya; Langiewicz, Magda; Jumaa, Hassan et al. (2015) Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 61:171-83|
|Glidewell-Kenney, Christine A; Trang, Crystal; Shao, Paul P et al. (2014) Neurokinin B induces c-fos transcription via protein kinase C and activation of serum response factor and Elk-1 in immortalized GnRH neurons. Endocrinology 155:3909-19|
|Thackray, Varykina G (2014) Fox tales: regulation of gonadotropin gene expression by forkhead transcription factors. Mol Cell Endocrinol 385:62-70|
|Breen, Kellie M; Mellon, Pamela L (2014) Influence of stress-induced intermediates on gonadotropin gene expression in gonadotrope cells. Mol Cell Endocrinol 385:71-7|
|Collins, Jessicah S; Beller, Jennifer P; Burt Solorzano, Christine et al. (2014) Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia. J Clin Endocrinol Metab 99:2887-96|
|McGee, W K; Bishop, C V; Pohl, C R et al. (2014) Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306:E1292-304|
|Ahow, Maryse; Min, Le; Pampillo, Macarena et al. (2014) KISS1R signals independently of G?q/11 and triggers LH secretion via the ?-arrestin pathway in the male mouse. Endocrinology 155:4433-46|
|Tolson, Kristen P; Garcia, Christian; Yen, Stephanie et al. (2014) Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest 124:3075-9|
|Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam et al. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513:436-9|
|Di Giorgio, Noelia P; Semaan, Sheila J; Kim, Joshua et al. (2014) Impaired GABAB receptor signaling dramatically up-regulates Kiss1 expression selectively in nonhypothalamic brain regions of adult but not prepubertal mice. Endocrinology 155:1033-44|
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