Long-term objectives of the proposed research are to determine the mechanism whereby ovine interferon tau (oIFN-tau) regulates expression of estrogen receptors in the uterus and to employ this knowledge in designing applications of oIFN-tau for the treatment of disease and cancer. Interferon-tau is a novel subclass of Type I interferons which is produced by the trophoblast cells of ruminant conceptuses and is the signal for maternal recognition of pregnancy in sheep, cattle and goats. Pregnancy recognition in these ruminants is a multifaceted physiological process involving conceptus-derived IFN-tau and endometrial hormone receptors for estrogen, progesterone and oxytocin. Recent studies from our laboratory indicate that oIFN-tau acts in an antiestrogenic manner to suppress estrogen receptor gene transcription in the endometrial epithelium which inhibits oxytocin receptor formation and luteolysis in sheep. Type I interferons are the therapeutic drug of choice for treatment of many viral diseases, such as hairy cell leukemia, and may also be useful for the treatment of solid tumors in the breast, ovary, and prostate. Ovine IFN-tau has potent antiviral, antitumor, antiproliferative and immunomodulatory properties similar to those of classical Type I interferons (alpha and beta), but it lacks their cytotoxic properties even at the high levels found within the uterus during early pregnancy. Proposed research will contribute to a more complete understanding of the cellular and molecular physiology of hormone receptor expression in the ovine uterus, particularly the regulatory actions of IFN-tau on uterine estrogen receptor expression. Because oIFN-tau suppresses estrogen receptor gene transcription and is less cytotoxic than other Type I IFNs, results of the proposed research are necessary to develop IFN-tau as a novel therapeutic agent for the treatment of disease and cancer in humans. The proposed research will delineate cellular and molecular mechanisms whereby IFN-tau regulates expression of estrogen receptors in the ovine uterus.
Specific aims are to: (1) determine effects of pregnancy and intrauterine injection of recombinant olFN-tau on endometrial estrogen receptor gene transcription; (2) clone a full-length cDNA for the ovine estrogen receptor mRNA and the ovine estrogen receptor gene; and (3) identify and characterize interferon-stimulated responsive elements (ISREs) that regulate transcription of the ovine estrogen receptor gene using in vitro and in vivo analyses of the 5' promoter/enhancer region.
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