February 21, 2003

Reproductive division continues work with renewed funding

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S.K. Dey, Ph.D.

Reproductive division continues work with renewed funding

Sanjoy K. Das, Ph.D.

Sanjoy K. Das, Ph.D.

The early days of a pregnancy are precarious, with success relying on the orderly development of the burgeoning embryo, the proper preparation of the uterine bed, and the fragile embryo finding secure lodging there. The process is so complex, it borders on the miraculous.

Teasing apart the mechanisms coordinating this web of events is the focus of researchers in Vanderbilt’s division of Reproductive and Developmental Biology. The scientists’ efforts were given a boost recently by the renewal of two NIH-funded grants, each of which provides $1.5 million of funding over a five-year period.

S. K. Dey, Ph.D., Dorothy Overall Wells Professor of Pediatrics and professor of Cell & Developmental Biology and Pharmacology, received funding from the National Institute on Drug Abuse for his studies on endocannabinoid signaling during early pregnancy. Sanjoy K. Das, Ph.D., associate professor of Pediatrics, received funding from the National Institute of Environmental Health Sciences to study estrogen-mimicking environmental toxins and uterine gene expression.

Dey, who moved from the University of Kansas last summer to head up the new division, is pleased with the successful renewals, and with the collaborative environment he and the colleagues who relocated with him have found here at Vanderbilt.

“We are very excited to further invigorate our continuing collaboration with Ray DuBois, Jason Morrow and Larry Marnett on various aspects of prostanoid, endocannabinoid and environmental estrogen research,” said Dey.

Renewal of the NIDA grant will allow Dey to further explore how signaling by anandamide, a suspected endogenous cannabinoid, synchronizes embryonic development and uterine receptivity for successful implantation. Cannabinoids are molecules like those extracted from the marijuana plant, Cannabis sativa, known to elicit various psychophysiological responses in animals and humans. Anandamide is an alternative name for the chemical arachidonoylethanolamine, and is derived from the Sanskrit word anand, meaning “bliss.”

Previous findings from Dey’s lab showed that the mouse pre-implantation embryo, or blastocyst, has significant numbers of cannabinoid receptors. Moreover, anandamide is produced in the uterus and is capable of activating those receptors. The studies also provided evidence that levels of uterine anandamide and of blastocyst CB1 receptors drop, due to downregulated gene expression, before implantation. Higher levels of anandamide in the uterus inhibit blastocyst growth.

Das’ NIEHS award will support continuing studies on estrogen’s role in preparing the uterus for embryo implantation. An “early” (within six hours of estrogen injection) and “late” (from 18 to 30 hours post-injection) biphasic estrogen response in the mouse uterus has been recognized for more than 60 years, yet mechanisms involved in its regulation remain controversial, said Das.

Most theories make the assumption that all responses to estrogen are dependent upon interaction with one of two known estrogen receptors (ER-alpha and ER-beta). Das’ lab, however, has recently identified several downstream target genes regulated early on by estrogen in the uterus by an ER-independent mechanism. The researchers also found that by injecting a selective MAP kinase inhibitor, gene expression is altered in a way that allows study of early and late estrogenic responses separately, and provides the means to determine the relationship between the two phases.

With the additional funding, the lab will explore the hypothesis that early responses to estrogen are ER-independent, that late responses are ER-dependent, and that cooperation between the two phases is necessary for a full complement response in the uterus to either natural or environmental sources of estrogen.