The goals of the proposed research are to identify specific cell types which possess receptors for insulin-like growth factors (IGF's) in the human retina and to determine if binding of IGF-I and IGF-H to these cells is abnormal in diabetic retinopathy. The overall hypothesis is that vascular IGF receptors are abnormally regulated in diabetetic retinopathy (DR). The present proposal is part of a plan to change the direction of my research program to a major emphasis on vision research, particularly in relation to diabetes and metabolism. 1(GF-I and -II receptors are present in the brain but the distribution of IGF receptors among the different cell types in the intact retina is unknown. Our preliminary results on bovine and rat retinas show that IGF-II receptors are concentrated in the retinal pigment epithelium, choroid, and sclera whereas IGF-I receptors are found mainly in the neural retina aid choroid. The proposed research is a high risk pilot study aimed at determining if IGF binding to specific vascular or neural cells is altered in DR. Specific Aim No.1 addresses the question: "Which cells in the retina possess receptors for IGF's?" The methods will involve: (a) autoradiography of 125I-IGF-I and -II binding sites; (b) immunostaining with IGF receptor antibodies, esp. the widely used a-IR3 monoclonal antibody against the human IGF-I receptor for IGF-I receptors and the R- II-PAB1 polyclonal antiserum against the rat IGF-11 receptor (binds to human IGF-II receptor); (c) electron microscopic (EM) studies with biotinylated IGF'S, and EM immunostaining with the anti-receptor antibodies. Specific Aim No. 2 addresses the question, "Are there changes in numbers, location, or binding properties of IGF receptors associated with specific cell types of the retina in diabetic retinopathy?" We will use retinas from DR donors (both sexes, ages 45-70) obtained from the Lions Eye Bank, U.W. The vascular changes associated with DR eventually affect most individuals with diabetes and lead to blindness or visual impairment in a high proportion of diabetics with DR.The primary causes of basement membrane thickening in retinal microvessels, retinal capillary proliferation and the breakdown of the endothelial cell barrier and pericyte function in DR are unknown. The proposed research on retinal growth factor receptors will improve our understanding of the cellular abnormalities in the retina of patients with diabetic retinopathy.
NIH ExPorter
NIH ExPorter