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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Biology Study Section (REB)
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Yoshinaga, Koji
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Texas Agrilife Research
Veterinary Sciences
Schools of Earth Sciences/Natur
College Station
United States
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Bazer, Fuller W; Burghardt, Robert C; Johnson, Gregory A et al. (2018) Mechanisms for the establishment and maintenance of pregnancy: synergies from scientific collaborations. Biol Reprod 99:225-241
Bazer, Fuller W; Thatcher, William W (2017) Chronicling the discovery of interferon tau. Reproduction 154:F11-F20
Song, Gwonhwa; Fleming, Jo-Ann G W; Kim, Jinyoung et al. (2011) Pregnancy and interferon tau regulate DDX58 and PLSCR1 in the ovine uterus during the peri-implantation period. Reproduction 141:127-38
Song, G; Fleming, J-A G W; Kim, J et al. (2011) Pregnancy and interferon tau regulate N-myc interactor in the ovine uterus. Domest Anim Endocrinol 40:87-97
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Song, Gwonhwa; Satterfield, M Carey; Kim, Jinyoung et al. (2009) Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy. Reproduction 137:553-65
Bazer, Fuller W; Spencer, Thomas E; Johnson, Greg A et al. (2009) Comparative aspects of implantation. Reproduction 138:195-209
Ahn, Hyo Won; Farmer, Jennifer L; Bazer, Fuller W et al. (2009) Progesterone and interferon tau-regulated genes in the ovine uterine endometrium: identification of periostin as a potential mediator of conceptus elongation. Reproduction 138:813-25
Fleming, Jo-Ann G W; Song, Gwonhwa; Choi, Youngsok et al. (2009) Interferon regulatory factor 6 (IRF6) is expressed in the ovine uterus and functions as a transcriptional activator. Mol Cell Endocrinol 299:252-60
Bazer, Fuller W; Burghardt, Robert C; Johnson, Greg A et al. (2008) Interferons and progesterone for establishment and maintenance of pregnancy: interactions among novel cell signaling pathways. Reprod Biol 8:179-211

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