INFLUENZA OR FLU IS ONE OF TOP 3 ECONOMIC DISEASES AFFECTING THE PORK INDUSTRY. IN HUMANS, IT CAUSES UP TO 41,000 HUMAN FATALITIES IN UNITED STATES AND UPWARDS OF 500,000 CASUALTIES WORLDWIDE. PIGS SERVE AS RESERVOIRS FOR SWINE, AVIAN, AND HUMAN VIRUSES AND PRODUCE NOVEL HIGH POTENCY STRAINS, SIMILAR TO THE "SWINE FLU" PANDEMIC H1N1 STRAIN. OUR HYPOTHESIS IS THAT ELIMINATING RECEPTORS FOR VIRAL ENTRY AND INTERFERING WITH VIRAL REPLICATION WILL SERVES AS A DUAL MECHANISM FOR PROTECTING THE PIGS FROM VIRAL INFECTION, AND TRANSMISSION OF FLU TO HUMAN AND PIG HOSTS. THERE ARE THREE OBJECTIVES IN THE PROPOSAL: 1) ASSEMBLE AND VALIDATE GENOME EDITING TOOLS TO DELETE THE RECEPTOR FOR FLU VIRUS ENTRY, AND PREVENT VIRAL PROPAGATION; 2) GENERATE RECOMBINANT PIGS; AND 3) TEST THE RECOMBINANT PIGS FOR SUSCEPTIBILITY TO INFECTION BY SWINE AND HUMAN TYPE ADAPTED VIRUSES TO INFECTION AND DISSEMINATION. WE EXPECT TO DEVELOP A PIG MODEL OF INFLUENZA RESEARCH AND IDENTIFY DRUGGABLE TARGETS. FROM AGRICULTURAL STAND POINT, WE ANTICIPATE ELIMINATION OF FLU FROM COMMERCIAL SWINE HERDS.