During pathological neovascularization of the retina, normally quiescent vascular endothelial cells proliferate and migrate through the extracellular matrix (ECM), resulting in the formation of new blood vessels. If these newly formed vessels leak fluid, hemorrhage or are associated with fibrous proliferation, retinal edema, retinal/vitreous hemorrhage or traction retinal detachments may occur resulting in potentially catastrophic loss of vision. While many factors can stimulate endothelial cells to proliferate, the cells ultimately must navigate the ECM; during normal angiogenesis this is done in a highly ordered fashion resulting in the formation of functional blood vessels. During abnormal neovascularization of the iris, retina or choroid, angiogenesis is unregulated and usually results in the formation of dysfunctional blood vessels. The long term goal of this research program has been to understand the interaction between proliferating vascular endothelial cells, adhesion receptors and various components of the ECM. More recently we have explored the role of several other cell types critical to the regulation of retinal angiogenesis. One of these cells, adult bone marrow derived lineage negative hematopoietic stem cells (Lin-HSC), exert profound vasculo- and neurotrophic rescue in models of vascular and retinal degeneration. Thus, autologous cell based therapy may be useful in the treatment degenerative of eye diseases if underlying mechanisms of angiogenesis and Lin-HSC homing were better understood. We will accomplish this through the following specific aims: (1) study the role of integrins and other adhesion receptors during ocular angiogenesis; (2) examine the mechanism whereby Lin-HSC exert vasculo- and neurotrophic rescue in several models of vascular and neural retinal degenerations; and (3) use selectively targeting HSC transfected with siRNAs and plasmids to create conditional knockdowns useful for the study of ocular angiogenesis. These studies will provide insights into mechanisms of angiogenesis that will be useful for the prevention and treatment of neovascular eye diseases.