Project Grant R01HL169447

PERIVASCULAR MACROPHAGES - A NEW PLAYER IN REGULATING ENDOTHELIAL REPAIR FOLLOWING LUNG VASCULAR INJURY - PROJECT SUMMARY / ABSTRACT ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS A SEVERE FORM OF ACUTE LUNG INJURY (ALI), CHARACTERIZED BY INJURY TO ENDOTHELIAL CELLS (ECS) IN THE LUNGS THAT LEADS TO VASCULAR LEAKAGE AND PULMONARY EDEMA. CURRENTLY, EFFECTIVE TREATMENTS FOR ARDS ARE LACKING, HIGHLIGHTING THE URGENT NEED FOR INNOVATIVE STRATEGIES THAT FOCUS ON REJUVENATING EC REGENERATION AND REPAIRING BLOOD VESSELS. PERIVASCULAR MACROPHAGES (PVMS), A SPECIFIC SUBSET OF MACROPHAGES LOCATED NEAR BLOOD VESSELS, ARE KNOWN TO INFLUENCE VASCULAR FUNCTION. HOWEVER, THEIR SPECIFIC ROLE IN ENDOTHELIAL REPAIR DURING ARDS REMAINS UNCLEAR. THIS STUDY AIMS TO INVESTIGATE THE HYPOTHESIS THAT PVMS PLAY A CRITICAL ROLE IN PROMOTING EC REGENERATION AND VASCULAR REPAIR FOLLOWING ALI/ARDS. THE SPECIFIC AIMS ARE AS FOLLOWS: 1) TO DETERMINE THE REGULATORY ROLE OF PVMS IN PROMOTING EC REGENERATION AND VASCULAR REPAIR AFTER ALI, WE WILL USE INTRAVITAL MICROSCOPY IMAGING TO OBSERVE THE DYNAMIC INTERACTIONS BETWEEN PVMS AND ECS IN LIVE MOUSE LUNGS. WE WILL CONDUCT LOSS-OF-FUNCTION STUDIES BY GENETICALLY REMOVING PVMS FROM THE LUNGS, AND GAIN-OF-FUNCTION STUDIES BY TRANSFERRING PVMS INTO LUNGS USING ALI MODELS. 2) TO ELUCIDATE THE SPECIFIC MECHANISMS THROUGH WHICH PVMS CONTRIBUTE TO ENDOTHELIAL REGENERATION AND VASCULAR REPAIR, WE WILL INVESTIGATE THE INVOLVEMENT OF EXOSOMES RELEASED BY PVMS AND THEIR PRIMARY CARGO, GLUTAMINASE, IN FACILITATING COMMUNICATION BETWEEN PVMS AND ECS. ADDITIONALLY, WE WILL EXPLORE THE IMPACT OF GLUTAMINE METABOLISM AND ASSOCIATED CHANGES IN EPIGENETIC REGULATION WITHIN ECS, WHICH ARE DRIVEN BY EXOSOMAL GLUTAMINASE AND CRUCIAL FOR PROMOTING EC REGENERATION. THE OUTCOMES OF THIS PROJECT WILL HAVE SIGNIFICANT IMPLICATIONS FOR THE FIELDS OF MACROPHAGE BIOLOGY AND ENDOTHELIAL RESEARCH. ULTIMATELY, THIS STUDY AIMS TO IDENTIFY NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF ARDS, ADDRESSING THE CRITICAL NEED FOR EFFECTIVE INTERVENTIONS IN THIS LIFE-THREATENING CONDITION.