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Molecular and Integrated Systems Physiology of Prolactin

Christensen, Heather R.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040076

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Prolactin (PRL) is a 23-kDa hormone involved in several physiological processes, including lactation, mammary gland development, and female fertility. Dynamic secretory patterns of this hormone throughout the female reproductive cycle are known, although the precise details that underlie these profiles have not been fully elucidated. Here, we have show that the inhibition of PRL release from lactotroph cells of the anterior pituitary (AP) gland is dependent on the activation of a G-protein coupled inward-rectifying K+ (GIRK) channel by hypothalamic dopamine. We also demonstrate for the first time that this activation, which takes place on a unique day of the rodent estrous cycle (proestrus), is dependent on rising estrogen levels during the preceding day (diestrus). In addition to its dynamic secretion profiles, PRL has also been implicated in numerous diseases, including immune disorders and breast cancer. However, current mouse models demonstrate a limited capacity to study the role of PRL, as the gene expression and secretory profile of PRL differ between rodent and human. Thus, there is an acute need for a more relevant model with which to study the role of human PRL in normal and pathophysiology. To this end, we have generated transgenic mice that express the entire human PRL (hPRL) gene, driven by the pituitary promoter (present in rodents and humans) and extrapituitary-promoter (found only in primates). These “PRL-humanized” mice express hPRL within the AP gland as well as extrapituitary tissues of immune- and reproductive-origin (the spleen, mammary gland, uterus, testis, and prostate). Characterization studies show that the translated hPRL protein is present and responds to known physiological stimuli both in vitro and in vivo. Importantly, the expression of hPRL in female mice lacking endogenous mouse hormone (mPRL-/-) is able to rescue known reproductive defects (infertility, impaired mammary gland development, and the inability to lactate). On this mPRL-/- genetic background, hPRL-transgenic females are “normal” in all aspects of their reproductive physiology: time to vaginal opening (reproductive puberty in rodents), gestation, litter size, and lactation status. Implications for an immune-response of hPRL in these animals are also described. Together, these studies validate the usefulness of these our as a superior model to study human PRL physiology and pathophysiology.
Karen Gregerson, PhD (Committee Chair)
Robert Banks, PhD (Committee Member)
Arthur Buckley, PhD (Committee Member)
Nelson Horseman, PhD (Committee Member)
Sohaib Khan, PhD (Committee Member)
Yana Zavros, PhD (Committee Member)
Manabu Matsuda, PhD (Committee Member)
204 p.
Physiological Psychology
prolactin; bacterial artificial chromosome; GIRK; reproduction

Recommended Citations

Citations

  • Christensen, H. R. (2011). Molecular and Integrated Systems Physiology of Prolactin [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040076

    APA Style (7th edition)

  • Christensen, Heather. Molecular and Integrated Systems Physiology of Prolactin. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040076.

    MLA Style (8th edition)

  • Christensen, Heather. "Molecular and Integrated Systems Physiology of Prolactin." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040076

    Chicago Manual of Style (17th edition)

ucin1314040076
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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.