NOMINEE: This proposal describes a three year training program to develop a candidate's academic career in Vascular Surgery centered at a VA medical center. The candidate spent 3 years in formal research training at the Minneapolis VA with an NIH F32 NRSA fellowship grant working on intimal hyperplasia, a pathologic form of vascular remodeling after surgical injury. From the fellowship, the candidate published 15 peer-reviewed publications, 8 as first author and 6 directly related to the NRSA project. The fellowship led to the successful defense of a PhD thesis. The candidate has continued his research interests through a translational approach to vascular remodeling assessing the mechanisms of vein remodeling after arteriovenous fistula (AVF) construction for renal failure patients. In the past year, the candidate has published 3 peer-reviewed manuscripts related to this area, 1 as first author. HYPOTHESIS: The candidate plans to test the hypothesis that monocyte-endothelial cell adhesion followed by transmigration induces endothelial barrier injury and impairs Matrix Metalloproteinase (MMP) production and activity, leading to the failure of AVF maturation. SPECIFIC OBJECTIVES: (1) To evaluate the biomarker role of MMPs and monocyte adhesion molecules in the blood and vein segment of hemodialysis patients for predicting AVF maturation. (2) To investigate the molecular mechanisms of monocyte-endothelial cell interactions in endothelial barrier dysfunction and MMP dysregulation, leading to fistula failure.
A vascular procedure where failure is more common (30-60% failure rate) than success is the surgical construction of a mature autogenous AVF for hemodialysis access. This project emphasizes the interactive roles of blood cells and endothelial cells in vascular injury, with a practical view on the identification of new diagnostic tools and molecular targets for improved AVF outcome. SUBJECT POPULATION: All Veteran patients with renal insufficiency or renal failure. PROCEDURES TO BE USED: Molecular analyses will be performed in vein segments and blood from patients undergoing hemodialysis access surgery. The following experimental procedures will be used to test the stated hypothesis: 7 Isolation and purification of monocyte isolation from peripheral blood. 7 Gelatinase zymography and Western immunoblot quantification of protein (MMPs) expression. 7 Flow cytometric measurement of adhesion molecules 7 Electric Cell-substrate Impedance Sensing (ECIS) technique 7 Transwell assays of monocyte transendothelial migration and endothelial permeability 7 Biostatistics: Multivariate analysis and survival analysis (vein maturation and duration) 7 Patient management and case report form management. SIGNIFICANCE OF POTENTIAL NEW FINDINGS: Important insight can be gained in describing the mechanism for vein remodeling after AVF construction. If reliable biomarkers can be developed, certain patients could potentially be selected for alternative hemodialysis access such as a primary bridge graft. Furthermore, greater insight into the mechanism could lead to clinical trials evaluating medical therapies that decrease monocyte-endothelial cell interactions, such as statins. If successful, maturation rates for AVF would improve and the need for repeat surgery minimized.