|BS||Clinical Chemistry||University of South Florida||Tampa, Fla.|
|PhD||Biochemistry||Duke University||Durham, N.C.|
Biochemical genetics and epigenetics of estrogens and related receptors.
I am the principal investigator and director of the MU Center for Botanical Interaction Studies. The MU Center for Botanical Interaction 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.
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 (ERα) and estrogen receptor-beta (ERβ)-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 ERα -minus mice. These estrogen-induced responses in an ERα-minus mouse are indicative of the existence of a potential new estrogen receptor, “ER-gamma”. 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 estrogens and the receptors, and then to identify the molecular mechanisms mediating these functions. To pursue these goals, we “knocked out” the estrogen receptor-alpha (ERα) gene in mice via homologous recombination and asked the following question: Would an ERα-minus mouse respond to any known estrogen, estrogen metabolite or exogenous (natural or synthetic) estrogen analog, if it lacked the classic full length ERα protein? If ERα -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-ERα /non-ERβ response proteins exist and that in transgenic ERα-minus mice we would see a response to estrogens, such as the catechol estrogens.
We have found in ERα-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, non-ERα/non-ERβ estrogen response proteins or receptors; and B) NCER “receptors” can be readily characterized in the ER-minus mouse backgrounds. Using these 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 ER-minus 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 ERα or the ERβ 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.
Clookey SL, Welly RJ, Shay D, Woodford ML, Fritsche KL, Rector RS, Padilla J, Lubahn DB, Vieira-Potter VJ. (2019). Beta 3 Adrenergic Receptor Activation Rescues Metabolic Dysfunction in Female Estrogen Receptor Alpha-Null Mice. Front Physiol. 10:9. doi: 10.3389/fphys.2019.00009. eCollection 2019. [PubMed]
Winn NC, Jurrissen TJ, Grunewald ZI, Cunningham RP, Woodford ML, Kanaley JA, Lubahn DB, Manrique-Acevedo C, Rector RS, Vieira-Potter VJ, Padilla J. (2019). Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver. Am J Physiol Endocrinol Metab. 316(2):E156-E167. doi: 10.1152/ajpendo.00259.2018. [PubMed]
Starkey NJE, Li Y, Drenkhahn-Weinaug SK, Liu J, Lubahn DB. (2018). 27-Hydroxycholesterol Is an Estrogen Receptor β-Selective Negative Allosteric Modifier of 17β-Estradiol Binding. Endocrinology. 159(5):1972-1981. doi: 10.1210/en.2018-00081. [PubMed]
Song H, Lu Y, Qu Z, Mossine VV, Martin MB, Hou J, Cui J, Peculis BA, Mawhinney TP, Cheng J, Greenlief CM, Fritsche K, Schmidt FJ, Walter RB, Lubahn DB, Sun GY, Gu Z. (2016). Effects of aged garlic extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells. Sci Rep. 6:35323. doi: 10.1038/srep35323. [PubMed]
Lei W, Browning JD Jr, Eichen PA, Folk WR, Sun GY, Lubahn DB, Fritsche KL. (2016). An Investigation into the Immunomodulatory Activities of Sutherlandia frutescens in Healthy Mice. PLoS One. 11(8):e0160994. doi: 10.1371/journal.pone.0160994. eCollection 2016. [PubMed]
Chuang DY, Simonyi A, Cui J, Lubahn DB, Gu Z, Sun GY. (2016). Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2. Neuromolecular Med. 18(3):415-25. doi: 10.1007/s12017-016-8419-5. [PubMed]
Sun GY, Li R, Cui J, Hannink M, Gu Z, Fritsche KL, Lubahn DB, Simonyi A. (2016). Withania somnifera and Its Withanolides Attenuate Oxidative and Inflammatory Responses and Up-Regulate Antioxidant Responses in BV-2 Microglial Cells. Neuromolecular Med. 18(3):241-52. doi: 10.1007/s12017-016-8411-0. [PubMed]
Lu Y, Starkey N, Lei W, Li J, Cheng J, Folk WR, Lubahn DB. (2015). Inhibition of Hedgehog-Signaling Driven Genes in Prostate Cancer Cells by Sutherlandia frutescens Extract. PLoS One. 10(12):e0145507. doi: 10.1371/journal.pone.0145507. eCollection 2015. [PubMed]