Angiogenesis

The growth of new blood vessels from preexisting capillaries (angiogenesis) contributes to the pathogenesis of many diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, the major causes of blindness. Understanding the molecular and cellular mechanisms that regulate angiogenesis and, how their alterations contribute to growth of new blood vessels, has significant clinical impact.

Dr. Nader Sheibani's laboratory has demonstrated that thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, is an important modulator of retinal vascular homeostasis. Mice deficient in TSP1 fail to undergo appropriate vascular pruning and remodeling during postnatal vascularization of the retina; as a result they exhibit increased retinal vascular density. This finding opens many new questions relating to the molecular and signaling mechanisms that mediate TSP1 activity. Dr. Sheibani's lab has prepared cultures of vascular cells, including endothelial cells (EC), pericytes/smooth muscle cells, and astrocytes from TSP1-/- and wild type mice. Their goal is to determine the role TSP1 plays in coordinating the interactions among these cells during postnatal vascularization of the retina. Gene array analysis of retinal EC, with and without TSP1, has also identified a number of genes whose expression is differentially regulated. They are determining how alterations in the expression of these genes impact retinal EC phenotype and angiogenesis. Similar studies are being performed addressing the function of other angiogenesis related genes including CYP1B1, PECAM-1, endoglin, and members of bcl-2 family of proteins.

In separate studies, Dr. Sheibani has discovered that TSP1 is present at a significantly high level in the vitreous and aqueous humors of normal eyes, but its level is decreased at these sites during diabetes. Therefore, changes in TSP1 levels during diabetes may contribute to the development and progression of diabetic retinopathy. Their current studies indicate that in the absence of TSP1, the development and progression of retinopathies, as well as nephropathies, are significantly exacerbated in a novel diabetic model. Utilizing these mice, Dr. Sheibani's lab is studying how lack of TSP1 exacerbates the development and progression of early diabetic retinopathies and nephropathies. Future studies will focus on the contribution of TSP1 to altered cell adhesive interactions that results in loss of vascular cells, leakiness of blood vessels, hypervascularization of the retina and kidney, and loss of vision and renal function in diabetes. Similar studies are being performed with another endogenous inhibitor of angiogenesis, pigment epithelium derived factor (PEDF). The results of these studies will have great impact not only in understanding the mechanisms which normally keep ocular and renal vasculature in check but also aid in the advancement and design of new therapies to prevent loss of vision and kidney function in diabetes.

Dr. Arthur Polans' research focuses on uveal melanoma, the primary malignancy originating in the eye. Cancer is a multistage process impacting on a large number of genes and their related cellular pathways. Recent advances in both biochemical and molecular methods make it possible to study the pathways which endow tumor cells with properties related to their malignant and metastatic phenotypes. Such studies can provide significant information about the course of the disease and about effective treatments.

Dr. Polans' laboratory is especially interested in angiogenesis, the process by which new blood vessels develop to support the growing malignancy. The lab is also studying the cellular pathways contributing to the efficacy of new chemotherapeutic agents and establishing the use of these novel agents in pre-clinical and clinical trials. These studies of an ocular tumor are leading to improved treatments of other types of cancer including neuroblastoma and breast cancer.