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THE DISCOVERY OF THE ROLE OF INTERFERON-TAU (IFNT) IN PREGNANCY RECOGNITION IS CONSIDERED A SEMINAL FINDING IN RUMINANT REPRODUCTION. ALTHOUGH THERE IS CONVINCING EVIDENCE THAT THE EFFECTS OF IFNT ARE MEDIATED THROUGH ITS INTERACTION WITH THE TYPE I INTERFERON RECEPTOR (IFNAR), NO ONE HAS DONE THE DEFINITIVE EXPERIMENT OF INACTIVATING IFNAR TO CONFIRM THAT: THERE IS NOT AN ALTERNATIVE PATHWAY FOR RESCUE OF THE CORPUS LUTEUM (CL); AND THAT RESCUE OF THE CL IS THE ONLY ESSENTIAL EFFECT OF IFNT. WE HAVE INACTIVATED THE GENE FOR ONE OF THE TWO CHAINS OF IFNAR, IFNAR2, AND CAN THEREFORE CRITICALLY TEST WHETHER IFNT HAS OTHER ESSENTIAL FUNCTIONS BEYOND RESCUING THE CL BY BLOCKING THE PULSATILE RELEASE OF PROSTAGLANDIN F2 ALPHA (PGF2A) BY ENDOMETRIAL EPITHELIAL CELLS. THIS PROPOSAL IS BASED ON THE GENERAL HYPOTHESIS THAT IFNAR DEFICIENT EWES WILL BE INFERTILE AND WILL MAKE AN EXCELLENT ANIMAL MODEL FOR STUDYING THE ESTABLISHMENT OF PREGNANCY IN RUMINANTS. THE SPECIFIC AIMS FOR THE PROJECT ARE: (1) TO ASSESS THE FERTILITY OF IFNAR DEFICIENT EWES TO RIGOROUSLY TEST THE PARADIGM FOR IFNT-MEDIATED PREGNANCY RECOGNITION IN RUMINANTS; AND (2) TO TEST WHETHER ADMINISTRATION OF EXOGENOUS PROGESTERONE CAN COMPENSATE FOR A LACK OF FUNCTIONAL IFNT RECEPTORS IN IFNAR DEFICIENT EWES. WE EXPECT TO FIND THAT IFNAR DEFICIENT EWES ARE INFERTILE AND THAT PREGNANCY IN THESE EWES CAN BE RESCUED BY PROVIDING EXOGENOUS PROGESTERONE. HOWEVER, IF ONE OR MORE OF THE IFNAR DEFICIENT EWES BECOME PREGNANT WITHOUT PROGESTERONE SUPPLEMENTATION, THAT WOULD SUGGEST THAT IFNAR SIGNALING IS NOT REQUIRED FOR ESTABLISHMENT OF PREGNANCY IN RUMINANTS AND WOULD CONSTITUTE A MAJOR PARADIGM SHIFT IN REPRODUCTIVE BIOLOGY. FURTHERMORE, IF PROGESTERONE SUPPLEMENTATION FAILS TO SUPPORT THE ESTABLISHMENT AND MAINTENANCE OR PREGNANCY IN IFNAR DEFICIENT EWES, THIS WOULD SUGGEST THAT IFNT HAS OTHER CRITICAL FUNCTIONS BEYOND RESCUING THE CL THAT ARE MEDIATED BY IFNAR. THIS PROJECT WILL RESULT IN A CHANGE IN KNOWLEDGE REGARDING OUR UNDERSTANDING OF THE ROLE OF IFNT IN THE ESTABLISHMENT AND MAINTENANCE OF PREGNANCY IN RUMINANTS. ULTIMATELY, IT MAY RESULT IN NEW STRATEGIES TO IMPROVE FERTILITY RATES AND PREGNANCY SUCCESS IN RUMINANTS.

$200,000FY2021National Institute of Food and AgricultureUSDA

Utah State University, Logan UT

Investigators

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THE DISCOVERY OF THE ROLE OF INTERFERON-TAU (IFNT) IN PREGNANCY RECOGNITION IS CONSIDERED A SEMINAL FINDING IN RUMINANT REPRODUCTION. ALTHOUGH THERE IS CONVINCING EVIDENCE THAT THE EFFECTS OF IFNT ARE MEDIATED THROUGH ITS INTERACTION WITH THE TYPE I INTERFERON RECEPTOR (IFNAR), NO ONE HAS DONE THE DEFINITIVE EXPERIMENT OF INACTIVATING IFNAR TO CONFIRM THAT: THERE IS NOT AN ALTERNATIVE PATHWAY FOR RESCUE OF THE CORPUS LUTEUM (CL); AND THAT RESCUE OF THE CL IS THE ONLY ESSENTIAL EFFECT OF IFNT. WE HAVE INACTIVATED THE GENE FOR ONE OF THE TWO CHAINS OF IFNAR, IFNAR2, AND CAN THEREFORE CRITICALLY TEST WHETHER IFNT HAS OTHER ESSENTIAL FUNCTIONS BEYOND RESCUING THE CL BY BLOCKING THE PULSATILE RELEASE OF PROSTAGLANDIN F2 ALPHA (PGF2A) BY ENDOMETRIAL EPITHELIAL CELLS. THIS PROPOSAL IS BASED ON THE GENERAL HYPOTHESIS THAT IFNAR DEFICIENT EWES WILL BE INFERTILE AND WILL MAKE AN EXCELLENT ANIMAL MODEL FOR STUDYING THE ESTABLISHMENT OF PREGNANCY IN RUMINANTS. THE SPECIFIC AIMS FOR THE PROJECT ARE: (1) TO ASSESS THE FERTILITY OF IFNAR DEFICIENT EWES TO RIGOROUSLY TEST THE PARADIGM FOR IFNT-MEDIATED PREGNANCY RECOGNITION IN RUMINANTS; AND (2) TO TEST WHETHER ADMINISTRATION OF EXOGENOUS PROGESTERONE CAN COMPENSATE FOR A LACK OF FUNCTIONAL IFNT RECEPTORS IN IFNAR DEFICIENT EWES. WE EXPECT TO FIND THAT IFNAR DEFICIENT EWES ARE INFERTILE AND THAT PREGNANCY IN THESE EWES CAN BE RESCUED BY PROVIDING EXOGENOUS PROGESTERONE. HOWEVER, IF ONE OR MORE OF THE IFNAR DEFICIENT EWES BECOME PREGNANT WITHOUT PROGESTERONE SUPPLEMENTATION, THAT WOULD SUGGEST THAT IFNAR SIGNALING IS NOT REQUIRED FOR ESTABLISHMENT OF PREGNANCY IN RUMINANTS AND WOULD CONSTITUTE A MAJOR PARADIGM SHIFT IN REPRODUCTIVE BIOLOGY. FURTHERMORE, IF PROGESTERONE SUPPLEMENTATION FAILS TO SUPPORT THE ESTABLISHMENT AND MAINTENANCE OR PREGNANCY IN IFNAR DEFICIENT EWES, THIS WOULD SUGGEST THAT IFNT HAS OTHER CRITICAL FUNCTIONS BEYOND RESCUING THE CL THAT ARE MEDIATED BY IFNAR. THIS PROJECT WILL RESULT IN A CHANGE IN KNOWLEDGE REGARDING OUR UNDERSTANDING OF THE ROLE OF IFNT IN THE ESTABLISHMENT AND MAINTENANCE OF PREGNANCY IN RUMINANTS. ULTIMATELY, IT MAY RESULT IN NEW STRATEGIES TO IMPROVE FERTILITY RATES AND PREGNANCY SUCCESS IN RUMINANTS. · GrantIndex