Project Summary/Abstract: Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness in the world. Diabetic macular edema (DME) and retinal neovascularization (NV) are the 2 major pathological alternations leading to the vision loss in diabetic retinopathy. Angiogenesis and inflammation play a crucial role in the pathogenesis of DR. Inflammatory cells infiltrated into diabetic retina, leukostasis and secreted pro-angiogenetic cytokines are responsible for capillary non-perfusion, local ischemia and subsequent retinal vascular hyper-permeability and endothelial cell proliferation. Currently, there is no non-invasive, economic and effective therapy available for retinal NV and DME. Linomide, a novel water-soluble organic molecule, has been shown to have both anti-inflammatory and anti-angiogenic activities. It is used for preventing autoimmune diseases and inhibiting tumor growth. The anti-inflammatory and anti-angiogenic effects of Linomide has not been reported in the treatment of DR. Recently, our collaborator has synthesized a novel Linomide analog (Linomide 5) by replacing the N-methyl groups in Linomide with H. Linomide 5 has exhibited significantly more potent specific anti-proliferative activity and suppressed experimental choroidal neovascularization (CNV) in rats. We hypothesize that this novel Linomide analog has therapeutic potential in the treatment of DME and retinal NV. Our objective is to develop more potent, specific anti-inflammatory and anti-angiogenic drugs, which can prevent and arrest the retinal vascular leakage and NV. The Phase I project will determine the efficacy of this novel compound on the expression of inflammatory factors and retinal vascular leakage in animal models of DR. We will determine whether the intravitreal administration of Linomide can reduce retinal leukostasis and pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF-a), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1) in STZ- diabetic rats. We will also study the effect of novel Linomide analog on retinal vascular endothelial growth factor (VEGF) expression and vascular permeability in an OIR rat model. These studies have potential to identify a novel compound with therapeutic potential for the treatment of retinal NV and DME. In Future Phase II studies, we will focus on toxcicty and pharmacokinetic studies to develop new anti-angiogenic and anti-inflammatory drugs. Therefore, this project, if funded, has potential to generate a marketable product for the treatment of a major blinding disease. As retinal NV and DME affect a large population, and there is no effective drug available, these new anti-angiogenic drugs should have great commercial potential. Project Narrative: Angiogenesis and inflammation play a key role in the pathogenesis of diabetic retinopathy, which is a leading cause of blindness in the world. We will study the effect of a new compound (Linomide5) on retinal inflammation and angiogenesis in diabetic animal models. The purpose of this project is to develop a specific and effective drug, which can prevent and treat the retinal complications in diabetic patients. [unreadable] [unreadable] [unreadable] [unreadable]