Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT: Over 700,000 Americans live with end-stage kidney disease (ESKD) and more than 1 million are projected for 2030. Ninety percent of these patients depend on a functional vascular access for hemodialysis (HD) treatments. However, the high rate of failure and complications of HD accesses is one of the most common causes of morbidity in this vulnerable population. Approximately 70% of new ESKD patients initiate HD with a central venous catheter (CVC), and most continue on a catheter for the next 6 months despite the high risk of life- threatening bloodstream infections. One of the factors contributing to prolonged CVC use is the high rate of arteriovenous fistula (AVF) maturation failure. Up to 50% of newly created AVFs fail to mature independently due to significant stenoses (narrowing) in the venous segment. Interestingly, prior CVC use is significantly associated with AVF maturation failure. In this proposal, I will challenge the high-risk, high-reward hypothesis that AVF maturation failure after CVC use has a preventable immunological basis. Namely, this discovery and mechanistic proposal aims to demonstrate the mechanistic link between CVC-derived molecular patterns, exaggerated activation of neutrophils, and increased vascular damage in newly created fistulas. This proposal is built on strong scientific premises, including the increased expression of at least 20 neutrophil enriched genes in human veins that failed compared to veins that remodeled successfully after AVF creation. I hypothesize that activation of the FPR1 receptor by catheter-derived bacterial peptides primes circulating neutrophils prior to AVF creation, increases vascular infiltration, and causes an overresponse to postoperative vascular injury that contributes to AVF failure. The proposal is organized in three complementary Specific Aims (SA). A discovery SA will look for CVC-related changes in peripheral neutrophils of patients undergoing surgery for AVF creation using single-cell RNA sequencing. A mechanistic SA will dissect the role of catheter derived N-formylated peptides in neutrophil activation, and the consequences of this inflammatory pathway for postoperative AVF remodeling using genetically modified animal models. Lastly, a pre-clinical translational SA will create a relevant animal model that combines CVC insertion, biofilm formation, and AVF creation, and test the efficacy of FPR1 activation blockers and neutrophil-depleting therapies to improve AVF remodeling. Considering the frequent use of catheters in HD patients, results from this grant may not only be significant for AVF maturation outcomes but also for other postsurgical scenarios such as transplant injury. From the career development point of view, this application responds to Funding Opportunity Announcement PAR-21-313, which aims at facilitating the transition of new investigators of diverse and underrepresented backgrounds such as myself to research independence. This proposal will support the development of a novel scientific niche in vascular access research and will generate state-of-the-art data for competitive R01 applications.
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).
