Research Interests

I am the Principle Investigator and Director of the MU Center for Phytonutrient and Phytochemical Studies. The MU Center for Phytonutrient and Phytochemical Studies is a comprehensive research program that investigates the molecular mechanisms of phytochemicals and phytonutrients in human disease. The Center fosters research to determine the safety and efficacy of botanicals or plants in the treatment of human disease. The Center’s current research investigates molecular mechanisms of the phytoestrogen, antioxidant, and polyphenol actions in three human diseases: Cancer, Neurodegenerative disease and Immune-mediated abnormalities. (Please refer to the Botanical Center web site at www.phyto-research.org for more detailed information.)

My long-term research interests involve the understanding of the mechanism of action of the sex steroids and their receptors, in particular the estrogen receptors. My lab's research goals use the estrogen receptor-alpha (ERa)-minus mice to look for new estrogen response pathways (i.e. novel estrogen receptors) and to find novel functional roles for the classic estrogen receptor. This is a hot research area for me because of the increased interest in environmental estrogens and our observations that some of these environmental estrogens are inducing responses in the ERa-minus mice. These estrogen-induced responses in an ERa-minus mouse are indicative of the existence of an additional estrogen receptor. Other major interests in my laboratory are: 1) The trinucleotide repeat genetic diseases, primarily because many trinucleotide repeats with unknown function are found in several of the steroid receptor genes; and, 2) The imprinting signals of endocrine disrupters, such as the environmental estrogens, especially those potentially acting via DNA-methylation signaling pathways.

The main long-term goals of my research program are to find novel functions for both estrogens and estrogen response proteins, and then to identify the molecular mechanisms mediating these functions. To pursue these goals, we "knocked out" the estrogen receptor-alpha (ERa) gene in mice via homologous recombination and asked the following question: Would an ERa-minus mouse respond to any known estrogen, estrogen metabolite or exogenous (natural or synthetic) estrogen analog, if it lacked the classic full length ERa protein? If ERa-minus mice did respond, then we would know that at least one estrogen response protein other than ER exists. The working hypothesis was that several non-ERa response proteins exist and that in transgenic ERa-minus mice we would see a response to estrogens, such as the catechol estrogens.

We have found in ERa-minus mice a uterine lactoferrin mRNA response to 4-hydroxyestradiol, methoxychlor and kepone, but not to estradiol. We now hypothesize that: A) 4-hydroxyestradiol and these other biologically important estrogens work through their own unique non-classical, estrogen response (NCER) proteins; and B) NCER "receptors" can be readily characterized in the ER-minus mouse background. Using this mouse model system we are characterizing the 4-hydroxyestradiol and methoxychlor responses and the putative 4-hydroxyestradiol and methoxychlor receptors. Specifically: Aim #1, Characterize lactoferrin mRNA response to 4-hydroxyestradiol and methoxychlor in ER-minus mice; Aim #2, Characterize the putative 4-hydroxyestradiol and methoxychlor receptors in primary ER-minus uterine cell cultures; Aim #3, Characterize potential responses to estradiol in ER-minus mice; Aim #4, Characterize estrogen responses unique to 4-hydroxyestradiol and methoxychlor; and Aim #5, Clone the putative 4-hydroxyestradiol and methoxychlor receptors.

Our working hypothesis is that estrogen responses in behavior, in bone, in glucose homeostasis, and in the reproductive, immune, and cardiovascular systems may not be mediated exclusively by the classical ERa or newly described ERb proteins, but by additional non-classical estrogen response (NCER) proteins. Studying specific mouse NCER proteins will lead to a better understanding of estrogen's developmental, physiological, behavioral, and biochemical roles in humans.

Research Awards and Fellowships [top]

1978-1980 National Research Service Award
1985 Young Investigator Award - Academy of Clinical Laboratory Physicians & Scientists
1987 Mellon Postdoctoral Fellowship
1988 National Institutes of Health Postdoctoral Fellowship
1989-1992 Pew Scholar in the Biomedical Sciences
1999 MU Provost Outstanding Junior Faculty Research and Creativity Activity Award

[top]