A Diabetic Retinopathy-Associated Vascular Permeability Factor

糖尿病视网膜病变相关血管通透性因子

基本信息

批准号：
10412038
负责人：
Wei Li
金额：
$ 38.8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412038
关键词：
Affect Alternative Therapies Angiogenesis Inhibitors Angiogenic Factor Animal Model Antibodies Binding Blindness Blood Vessels Data Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Endothelium Extravasation Eye Human Investigation Lead Ligands Monoclonal Antibodies Mus Neonatal Oxygen Pathogenesis Pathogenicity Pathologic Persons Pharmacotherapy Play Proteins Resistance Retina Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Safety Severities Therapeutic Therapeutic Monoclonal Antibodies Translations Treatment Efficacy Up-Regulation Vascular Diseases Vascular Endothelial Growth Factors Vascular Permeabilities Vision angiogenesis comparative diabetic improved inhibitor innovation macular edema neutralizing antibody neutralizing monoclonal antibodies new technology novel novel therapeutics prevent proliferative diabetic retinopathy ranibizumab retina blood vessel structure secretogranin III targeted treatment translational impact

项目摘要

Project Summary Diabetic retinopathy (DR) is a leading cause of vision loss, affecting nearly 100 million people worldwide. Vascular leakage factors and angiogenic factors play an important role in the pathogenesis of vision-threatening diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), respectively. Vascular endothelial growth factor (VEGF) inhibitors have been approved for DME but not PDR with limited therapeutic efficacy. Identification of additional pathological ligands may lead to development of novel therapies for DME and PDR. We recently discovered secretogranin III (Scg3) as a highly disease-associated pro-angiogenic factor that preferentially binds to and stimulates angiogenesis of diabetic but not normal vessels. In contrast, VEGF binds to and induces angiogenesis of both diabetic and normal vessels. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. control retinal vessels but the lowest binding to normal vasculature. Unlike VEGF upregulation in PDR, however, Scg3 expression minimally increases in diabetic retina. This project is to investigate a new pathogenic mechanism by which the upregulation of Scg3 selective binding to diseased vessels, but not ligand expression itself, exacerbates DR pathogenesis. In Aim 1, we will quantify and correlate Scg3 disease-related endothelial binding activity to the severity of DR leakage. In Aim 2, we will establish a correlation between Scg3 endothelial binding activity and the severity of pathological retinal neovascularization in mice. In Aim 3, a well-characterized Scg3-neutralizing monoclonal antibody with high therapeutic efficacy and safety will be humanized and analyzed for its activity to alleviate DR leakage and pathological retinal neovascularization. To our knowledge, Scg3 is the first highly selective angiogenic factor. Investigation of Scg3 and its pathogenic mechanism will facilitate the discovery and characterization of other ligands with similar disease selectivity. Humanization of anti-Scg3 antibody may lead to the development of a new class of “selective angiogenesis blockers” for the therapy of DR and other retinal vascular diseases.

项目概要糖尿病视网膜病变 (DR) 是视力丧失的主要原因，影响着全球近 1 亿人。血管渗漏因素和血管生成因素在视力威胁的发病机制中发挥重要作用分别为糖尿病性黄斑水肿（DME）和增殖性糖尿病性视网膜病变（PDR）。生长因子 (VEGF) 抑制剂已被批准用于 DME，但尚未批准用于 PDR，且治疗效果有限。其他病理配体的鉴定可能会导致 DME 和 PDR 新疗法的开发。我们最近发现分泌粒素 III (Scg3) 是一种与疾病高度相关的促血管生成因子，优先结合并刺激糖尿病血管而非正常血管的血管生成，相反，VEGF 则结合。并诱导糖尿病血管和正常血管的血管生成。与对照视网膜血管相比，Scg3 与糖尿病视网膜血管的结合活性比最高，但与然而，与 PDR 中的 VEGF 上调不同，Scg3 的表达在 PDR 中略有增加。该项目旨在研究 Scg3 上调的新致病机制。与病变血管的选择性结合，而非配体表达本身，会加剧 DR 发病机制。我们将量化 Scg3 疾病相关的内皮结合活性，并将其与 DR 渗漏的严重程度相关联。目标 2，我们将建立 Scg3 内皮结合活性与病理严重程度之间的相关性在 Aim 3 中，一种经过充分表征的 Scg3 中和单克隆抗体。高治疗功效和安全性将被人性化并分析其活性，以减轻 DR 泄漏和据我们所知，Scg3是第一个高度选择性的血管生成因子。 Scg3及其致病机制的研究将有助于其他疾病的发现和表征具有相似疾病选择性的配体可能会导致抗Scg3抗体的人源化。用于治疗 DR 和其他视网膜血管疾病的新型“选择性血管生成阻滞剂”。