Young Andrologist Award, Am. Soc. of Andrology, 1996, Presented annually by Am. Soc. of Andrology to the outstanding U.S. scientist in male reproductive biology under 40 years old.
Dr. Cooke's laboratory works in several areas of male and female reproductive biology. Our current major research interest is in the role of membrane estrogen receptor 1 (ESR1) in male and female reproductive biology. Most ESR1 in target tissues/cells is nuclear/cytoplasmic and signals through the canonical nuclear estrogen receptor pathway, which is essential for major reproductive effects of 17 beta-estradiol (E2). This involves E2 binding to nuclear ESR1, which is then phosphorylated and dimerizes, leading to translocation of ligand-receptor complexes to DNA, where they bind estrogen-response elements (EREs) in target genes. However, a small fraction (5-10%) of ESR1 protein produced is post-translationally palmitoylated and inserted into cell membranes; this mESR1 activates phosphoinositide 3-kinase/AKT (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathways in the cell membrane, and induces other effects.
Work in our laboratory currently centers on a powerful new transgenic mouse that we use to study the role of membrane ESR1 (mESR1) in E2 signaling. This new transgenic nuclear-only estrogen receptor 1 (NOER) mouse lacks mESR1 but still expresses nESR1. This mouse provides a unique tool to establish relative roles of mESR1 and nuclear ESR1 (nESR1) in E2 signaling. Critically, we have recently shown that male mice lacking mESR1 are infertile and have extensive endocrine and reproductive abnormalities, for the first time establishing a key role for mESR1 in E2 physiology. We are using these unique mice as one of our major tools to try to understand the role of mESR1 in E2 signaling.
Our laboratory has also developed a uterine-specific conditional knockout of the histone methyltransferase EZH2. Knockout of EZH2 in the uterus leads to constitutive luminal epithelial proliferation even in ovariectomized mice lacking estrogen. This new model will provide important insights into epigenetic regulation of estrogen response by EZH2 in the uterus, and the role of steroid hormones such as estrogen in uterine gene imprinting through epigenetic mechanisms.
Estrogen in the male: a historical perspective.
Biol Reprod. 2018 Jul 1;99(1):27-44. doi: 10.1093/biolre/ioy043.
Cunha GR, Kurita T, Cao M, Shen J, Cooke PS, Robboy S, Baskin L (2018) Tissue interactions and estrogenic response during human female fetal reproductive tract development. Differentiation 101:39–45.
*Nanjappa MK, Hess RA, Medrano TI, Locker SH, Levin ER, Cooke PS.
*This paper was selected as one of the Top Endocrine Discoveries for 2016 by a consortium of Endocrinology journals.
Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA.
Physiol Rev. 2017 Jul 1;97(3):995-1043. doi: 10.1152/physrev.00018.2016.