This application describes a 4 year training program that fosters the development of a career in academic research. The principal investigator is near completion of his post-doctoral training phase at the University of North Carolina and now requires broadening of his scientific skills with a brief mentoring phase before seeking independence as an investigator in the field of collateral remodeling in ischemia. The proposed research will focus on the biology of pre-existing collaterals under normal resting and ischemic conditions. This proposed research is related but divergent from the mentor's research. Recent work in the Faber laboratory compared two mouse strains that we observed have stark differences in collateral density, capacity to remodel and VEGF-A expression. This mouse strain-dependent difference establishes the C57BL/6 and BALB/c strains as excellent models for studying the determinants of collateral remodeling in ischemia. Proposed experiments in this application will use an assortment of cellular, molecular, and immunohistochemical techniques to study the biology of collateral wall cells, gene expression profiles and the genetic determinants that regulate the capacity of collaterals to remodel in an animal model of ischemia.
Specific aims i nclude: 1) Measure fundamental properties of collateral blood flow and determine if collateral endothelial cell orientation is stochastic and correlates with the tortuous pattern during collateral remodeling, 2) Identify the underlying genetic mechanisms that protect collaterals from expressing an inflammation-like and pro-thrombotic phenotype and that protect collaterals from vascular regression in a disturbed, slow and oscillatory flow environment, and 3) Investigate the basis for variation in the capacity of collaterals to remodel in ischemia using two genetically distinct mouse strains, the C57BL/6 and BALB/c. This proposal will provide the first morphologic and genetic analyses of collateral endothelial cells and begin to define how collaterals are protected from inflammation, thrombosis and vascular regression under a disturbed, slow and oscillatory flow environment. In addition, findings from this proposal will provide insight into the genetic basis for variation in capacity of collaterals to enlarge. The goal of the proposed research is to acquire new and important knowledge that may encourage new strategies to enhance the growth and stability of collateral vessels in patients with ischemic vascular disease.
| Chalothorn, Dan; Faber, James E (2010) Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics 42:469-79 |
