Thursday, April 18, 2024
4/18/2024
PROJECT SUMMARY Why patients with cystic fibrosis (CF) continue to suffer from chronic bacterial infections despite new medications that improve CF transmembrane conductance regulator (CFTR) function is not known. The long-term goal is to develop therapeutics that modulate host immune responses in CF patients to mitigate chronic infection and inflammation. The objective of this proposal is to define how CFTR regulates macrophage function. The rationale underlying this proposal is that our prior work demonstrates that CF macrophages are integral to the inability of patients with CF to clear bacterial infections through failed NADPH oxidase (NOX) assembly and reduced autophagy. The central hypothesis is that loss of functional CFTR in human MFs inhibits NOX assembly and subsequent ROS-mediated autophagy, independent of CFTR mutation class, but worsened by specific opportunistic bacteria. Further, we expect that a critical threshold of CFTR function is needed to reverse the NOX assembly/autophagy deficits and can be re-established by CFTR modulators combined with alternative CFTR restoration agents such as cysteamine or our novel autophagy stimulator, AR-13. The central hypothesis will be tested by pursuing three specific aims: 1) Define the mechanism by which CFTR regulates MF NOX assembly; 2) Determine how CF specific pathogens differentially regulate MF ROS production; 3) Determine the extent to which novel therapeutic approaches alter the MF NOX/autophagy axis. We will pursue these aims using an innovative combination of genetic and pharmacologic techniques in human macrophages. The proposed research is significant because a precise understanding of how CF macrophage function is regulated would allow novel antibiotic- and CFTR mutation- agnostic treatment approaches to infection. It is also significant because it will determine if specific pathogens independently contribute to deficits in macrophage-mediated bacterial killing. The expected outcome of this work will establish a mechanistic framework to enable us to target and correct defective CF MF-mediated bacterial killing. Ultimately, we will translate this new knowledge into a new treatment paradigm that uses innovative host-directed therapies to combat bacterial infections.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
