Progesterone is a steroid hormone of tremendous physiological importance. Not only does it play a central role in reproduction, but it also has neuroactive properties. Molecules that mimic or modulate the effects of progesterone (progestins and antiprogestins) in biological systems are of significant pharmaceutical importance, being most commonly used for birth control and in the treatment of cancer and endometriosis. Traditionally, the biological activity of such molecules has been tested by investigating their effects on the well studied nuclear progesterone receptor and their effects in the human body have been interpreted solely in this light. Recently, a new class of receptors for progesterone has been discovered that reside on the plasma membrane and it is likely that these receptors represent an additional in vivo target for progesterone-like molecules. Consequently, the characterization of these membrane progesterone receptors is likely to paint a clearer picture of the physiology of progesterone and the pharmacology of progesterone-like compounds. In this proposal, an assay system will be developed with which the biochemistry and pharmacology of this new class of progesterone receptor can be investigated. This will be achieved by expressing the human progesterone receptors in a simple model system called Saccharomyces cerevisiae. This system has the benefit of being able to functionally express these receptors and of not possessing other progesterone binding proteins that can interfere with analysis of the individual human membrane progesterone receptors. This system will first be used to probe the relationship between the structural aspects of these new receptors and their ability to bind progesterone and transduce signals inside cells. These membrane progesterone receptors sense extracellular progesterone and produce an intracellular second messenger that is responsible for the physiological changes inside cells. However, the identity of the second messenger produced by these receptors is unknown. Therefore, the second goal of this proposal will consist of identifying the chemical mechanism of signal transduction. Finally, the system can be used to screen large numbers of chemical compounds of pharmaceutical, dietary and environmental importance for their ability to activate or inhibit receptors in this particular class. These experiments will significantly expand our understanding of the biology of progesterone as well as the pharmacology and potential side-effects of progesterone-like pharmaceuticals. PUBLIC HEALTH REVELANCE: The steroid hormone, progesterone, and molecules that modulate its effects are of critical pharmaceutical and environmental importance. We have established a system through which we can investigate how such molecules affect a new family of hormone receptors that is largely unstudied. The studies outlined in this proposal will significantly expand our understanding of how human cells sense and respond to steroid hormones.

Public Health Relevance

The steroid hormone, progesterone, and molecules that modulate its effects are of critical pharmaceutical and environmental importance. We have established a system through which we can investigate how such molecules affect a new family of hormone receptors that is largely unstudied. The studies outlined in this proposal will significantly expand our understanding of how human cells sense and respond to steroid hormones.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086617-04
Application #
8214499
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$245,095
Indirect Cost
$66,499
Name
Foundation for Applied Molecular Evolutn
Department
Type
DUNS #
134136394
City
Gainesville
State
FL
Country
United States
Zip Code
32604
Moussatche, Patricia; Lyons, Thomas J (2012) Non-genomic progesterone signalling and its non-canonical receptor. Biochem Soc Trans 40:200-4
Villa, Nancy Y; Moussatche, Patricia; Chamberlin, Stephen G et al. (2011) Phylogenetic and preliminary phenotypic analysis of yeast PAQR receptors: potential antifungal targets. J Mol Evol 73:134-52
Kupchak, Brian R; Garitaonandia, Ibon; Villa, Nancy Y et al. (2009) Antagonism of human adiponectin receptors and their membrane progesterone receptor paralogs by TNFalpha and a ceramidase inhibitor. Biochemistry 48:5504-6