Project Grant R01HL171071

A NOVEL MECHANISM FOR POLYUNSATURATED FATTY ACID UPTAKE AND ACTION IN NEUTROPHILS - PROJECT SUMMARY / ABSTRACT: NEUTROPHILS ARE A MAJOR TYPE OF LEUKOCYTES THAT PLAY IMPORTANT ROLES IN ACUTE INFLAMMATION. THEY ARE TYPICALLY THE FIRST LEUKOCYTES TO BE RECRUITED TO INFLAMMATORY SITES AND CAN ELIMINATE PATHOGENS BY MULTIPLE MECHANISMS, INCLUDING RELEASING NEUTROPHIL EXTRACELLULAR TRAPS (NETS). ALTHOUGH NEUTROPHILS ARE IMPORTANT FOR NORMAL IMMUNE RESPONSES, PARTICULARLY TO MICROBIAL INFECTIONS, THEY ARE ALSO RESPONSIBLE FOR AND/OR CONTRIBUTE TO MANY INFLAMMATORY DISEASES, INCLUDING MYOCARDIAL ISCHEMIA-REPERFUSION INJURY (MIRI). IN OUR PRELIMINARY STUDIES, WE FOUND THAT NEUTROPHIL-SPECIFIC KO OF LRP5 (LRP5N) AGGRAVATES HEART INJURY IN THE MIRI MODEL BY ENHANCING NEUTROPHIL ACTIVATION. OUR PRELIMINARY RESULTS FURTHER INDICATE THAT LRP5 MAY FUNCTION AS A TRANSPORTER FOR POLYUNSATURATED FATTY ACIDS (PUFAS) AND IS REQUIRED FOR PUFA-MEDIATED INHIBITION OF MTORC1 SIGNALING IN NEUTROPHILS. IN THIS APPLICATION, WE PLAN TO DETERMINE HOW LRP5 TRANSPORTS PUFAS AND HOW IMPORTANT LRP5- TRANSPORTED PUFAS ARE FOR THE REGULATION OF NEUTROPHIL ACTIVITIES AND INFLAMMATION DISEASES RELATED TO NEUTROPHILS, INCLUDING MIRI.