Project Grant F30AI197787

THE ROLE OF B CELL DERIVED IL-1BETA SIGNALING IN THE BONE MARROW AND LUNGS - PROJECT SUMMARY/ABSTRACT THIS FELLOWSHIP PROPOSAL AIMS TO PROVIDE THE CANDIDATE WITH THE RESOURCES AND TRAINING TO PURSUE A CAREER AS AN INDEPENDENT PHYSICIAN SCIENTIST THROUGH THE EXPLORATION OF THE MECHANISMS DRIVING ANTIBODY SECRETING CELL (ASC) HOMEOSTASIS IN THE LUNGS AND BONE MARROW (BM). AN INNOVATIVE AND COMPREHENSIVE APPROACH HAS BEEN CRAFTED BY THE CANDIDATE TOGETHER WITH HER MENTORS TO MEET THESE GOALS AND PROVIDE A STRONG FOUNDATION FOR A CAREER IN TRANSLATIONAL RESEARCH. DISEASES OF THE LUNG RESULTING FROM RESPIRATORY PATHOGENS, AUTOIMMUNITY, AND ORGAN REJECTION REPRESENT LEADING CAUSES OF DEATH WORLDWIDE. ASCS PLAY A SIGNIFICANT ROLE IN THE RESOLUTION OF AND PROTECTION FROM RESPIRATORY INFECTION AS WELL AS IN THE PATHOGENESIS OF AUTOIMMUNE-INTERSTITIAL LUNG DISEASE AND ACUTE-ANTIBODY MEDIATED REJECTION. CYTOKINES AND CHEMOKINES ARE MASTER ORCHESTRATORS OF THE IMMUNE RESPONSE WHICH REGULATE THE DIFFERENTIATION OF B CELLS INTO ASCS AND FACILITATE THEIR TISSUE RESIDENCE/MIGRATION. INTERLEUKIN-1BETA (IL-1B) IS A CYTOKINE WHICH HAS BEEN IMPLICATED TO PLAY A ROLE IN ASC DEVELOPMENT, AND OUR LAB HAS DEMONSTRATED THAT B-CELLS AND ASCS EXPRESS IL-1B. THE ROLE OF B-CELL DERIVED IL- 1B ON ASC FORMATION AND MAINTENANCE HAS NOT YET BEEN EXPLORED. OUR PRELIMINARY STUDIES INDICATE THAT A B CELL-SPECIFIC LOSS OF IL-1B DECREASES LONG-LIVED ASCS IN THE BM AND THAT CIRCULATING ASCS HAVE LOWER LEVELS OF IL-1B THAN ASCS ISOLATED FROM THE LUNGS AND BM. THIS PROPOSAL WILL ASSESS THE ROLE OF B-CELL DERIVED IL-1B FOR ASC MIGRATION AND RETENTION IN THE BONE MARROW (SPECIFIC AIM 1) AND LUNGS (SPECIFIC AIM 2) USING INFLUENZA INFECTION AS A MODEL IN WHICH TO STUDY ASC DEVELOPMENT. THE CANDIDATE WILL HARNESS THE SUPPORT AND TRAINING FROM THIS PROPOSAL TO PURSUE A CAREER AS A PHYSICIAN SCIENTIST, WHERE FINDINGS FROM THE RESEARCH IN THIS PROPOSAL HAVE THE POTENTIAL TO REVEAL NOVEL OPPORTUNITIES FOR THERAPEUTICS THAT MODULATE ASC HOMEOSTASIS.