Translational and Computational Analysis of Dialysis Fistula Maturation Failure-2

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ABSTRACT Many of the insights into pathologic versus adaptive arterial remodeling have been achieved through a detailed understanding of the linkage between endothelial/smooth muscle cell biology and the local hemodynamic forces that modulate their response pattern. In the normal arterial circulation, where moderate shear stress, laminar flow patterns predominate, the response patterns following intervention have been well delineated and are the cornerstone for successful therapies. In contrast, the complex, high-energy, chaotic flow environment, which characterizes the AVF, breaks these established hemodynamic-biologic relationships. Aim 1 will explore the mechanosensing mechanisms that are instrumental in the interpretation of these forces and examine their downstream effect on shifting the smooth muscle cell (SMC) to a pro-proliferative, synthetic phenotype. In a more global sense, understanding the unique response patterns within the AVF flow environment are instrumental to moving the field forward and providing the needed insights to design the next generation of biologic therapies to improve AVF outcomes. Aims 2 and 3 will perform a systems-based analysis of the critical genomic changes that dictate successful versus failed AVF remodeling and utilize a multi-scale model to identify those key elements within the network that should move forward for further translational investigation. Supported by our preliminary data, we propose that the intima and media have unique response patterns following AVF creation. Using laser capture microdissection, high-throughput genomics and advanced network analysis, the current project will produce a multi-scale, computational model links changes in gene expression network to alterations in SMC and matrix biology and ultimately alterations in the remodeling response of the AVF architecture. Using this model, a systematic analysis of the biologic response to genomic perturbations can be explored, effectively performing a progression of in silico experiments to identify those key opportunities in the genomic response where the needed balance between expansive remodeling and modulated hyperplastic growth can be achieved. Within this context, the following Aims are proposed: SPECIFIC AIM 1: Explore the biomechanical linkage between AVF creation and SMC phenotype and evaluate the impact of these changes on AVF adaptation and successful (or failed) physiological maturation. SPECIFIC AIM 2: Delineate the changes in genome-wide expression patterns associated with AVF creation and identify unique genomic signatures that are associated with successful AVF remodeling. SPECIFIC AIM 3: Create and explore a dynamic gene regulatory network, which in combination with a multiscale computational model of vascular adaptation, identifies the subset of genes that have the most significant influence on augmenting outward remodeling and reducing intimal hyperplasia following AVF placement.