This Career Enhancement Award in Stem Cell Research will enable Dr. J. Koudy Williams to re-direct his research to stem cell approaches for the prevention and treatment of vascular disease. The proposed research plan combines the stem cell/regenerative medicine expertise of the Wake Forest University Institute of Regenerative Medicine (WFIRM) with the vascular biology/surgical expertise of Dr. Williams. Dr. Williams has institutional support for this award and has selected Dr. Shay Soker - a WFIRM core scientist whose expertise is the use of stem/progenitor cells in vascular research - as his sponsor. Dr. Williams has chosen co-investigators with expertise in vascular surgery (Dr. Geary), and biomechanics (Dr. Berry) who, with Dr. Soker, have devised a career development plan facilitating his current and future work in stem cell research. Over 500,000 coronary artery bypass grafts and 50,000 peripheral bypass grafts are performed annually in the United States due, in part, to complications of atherosclerotic disease. However, up to 30% of patients requiring arterial bypass surgery and other vascular procedures lack suitable or sufficient amounts of autologous graft material. We have shown that endothelial progenitor cells (EPCs) provide an endothelium and promote patency of bioengineered arteries for more than 4 months when used as carotid artery interposition grafts in sheep. However, the construction conditions of EPC-seeded bioengineered blood vessels in primates are currently unknown. The utility of primates in this research is critical because of their close phylogenetic, vascular disease susceptibility, and physiologic similarities to those of human beings. Our working hypothesis is that bioengineered blood vessels made from collagen scaffolds seeded with monkey EPCs and then used autologously to create an interpositional arterial graft will adapt to physiological flow conditions and mature in vivo to assume normal properties of native arteries. To address these questions, and test this hypothesis, we propose the following specific aims: 1) To construct blood vessels from collagen scaffolds seeded with EPCs from the bone marrow of monkey; and then 2) To examine the structural and functional properties of bioengineered vascular grafts when placed in nonhuman primates. Future directions of this research will be to extend this methodology to atherosclerotic nonhuman primates and examine the mechanisms regulating remodeling of the maturing bioengineered grafts. The proposed studies represent a stepping stone to the development of blood vessels to be used by individuals needing coronary artery bypass surgery, peripheral vascular surgery, and other vascular disorders. As such, these studies are an exciting and unique direction of research for Dr. Williams in collaboration with his colleagues at WFIRM.

K18HL087027

2007-02-05

2009-01-31