Proliferative diabetic retinopathy (PDR), characterized by aberrant neovascularization, is the leading cause of adult blindness in the United States. The devastating consequence of blindness in PDR is the result of aberrant neovascularization on the surface of the retina rather than physiological vascularization within the retina itself. It is now recognized that endothelial cell precursors circulate in the bloodstream, are recruited to sites of neoangiogenesis, and participate in new blood vessel formation. These precursors have been shown to express the chemokine receptor CXCR4 and migrate in response to stromal derived factor 1 (SDF-1). SDF-1 is a potent stimulator of vascular endothelial growth factor (VEGF), which is currently viewed as the major effector for retinal neovascularization in diabetic retinopathy. It is our hypothesis that PDR is the result of one or more defects in SDF- 1-mediated migration of endothelial progenitor cells leading to neoangiogenesis on the surface of the retina rather than within the retina. This proposal will address the following hypotheses: 1) Alterations in the pattern of SDF-1 in the retinas of diabetic patients or level of expression of CXCR4 on endothelial progenitor cells are evident in PDR; 2) Progenitor cells from patients with PDR have altered responses to SDF-1; and 3) Antagonism of SDF-/CXCR4 interactions will prevent retinal angiogenesis in vivo. These hypotheses will tested through the following Specific Aims:
Aim 1 : A) In diabetic patients, correlate the numbers of circulating endothelial cells and circulating endothelial progenitor cells by cell-based ELISA and correlate the expression of CXCR4 on these cells with the presence or absence of PDR; B) Examine the pattern of RNA expression of SDF-1 by in situ hybridization in cadaveric retinas of diabetic patients with and without PDR and normal controls; C) Determine the levels of SDF-1 in the vitreous fluid of diabetic patients with and without PDR and non-diabetic controls by ELISA.
Aim 2 : Examine SDF-1-dependent response of progenitor endothelial cells from diabetic patients with and without PDR and normal controls in a migration assay using a modified Boyden chamber, a tube formation assay on Matrigel, and an ELISA for VEGF expression.
Aim 3 : A) Examine the spatial and temporal expression of SDF-1 and CXCR4 in a neonatal mouse model of oxygen-induced retinopathy; B) Determine the effect of a CXCR4 antagonist on the development of retinal angiogenesis in an adult mouse model of induced retinopathy. These studies by bringing in expertise from the areas of chemokine and progenitor endothelial cell biology will provide important information on the pathogenesis of proliferative diabetic retinopathy.
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