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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：
10700261
负责人：
Wei Li
金额：
$ 25.1万
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/10700261
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.

项目摘要糖尿病视网膜病变（DR）是视力丧失的主要原因，影响全球近1亿人。血管渗漏因子和血管生成因子在视力威胁的发病机制中起重要作用糖尿病性黄斑水肿（DME）和增殖性糖尿病性视网膜病变（PDR）。血管内皮生长因子（VEGF）抑制剂已被批准用于DME，但未被批准用于疗效有限的PDR。其他病理配体的鉴定可能导致DME和PDR的新疗法的开发。我们最近发现分泌颗粒蛋白III（Scg 3）是一种高度疾病相关的促血管生成因子，优先结合并刺激糖尿病血管而不是正常血管的血管生成。相反，VEGF结合并诱导糖尿病和正常血管的血管生成。在数以千计的定量内皮细胞中，在配体中，Scg3对糖尿病视网膜血管与对照视网膜血管具有最高的结合活性比，但对正常的脉管系统然而，与PDR中VEGF上调不同，糖尿病视网膜本研究旨在探讨Scg3基因表达上调与肿瘤发生发展的关系，与患病血管的选择性结合而不是配体表达本身加剧了DR发病机制。在目标1中，我们将量化Scg3疾病相关的内皮结合活性并将其与DR渗漏的严重性相关联。在目的2，我们将建立Scg 3内皮结合活性与病理性血管病变严重程度之间的相关性，小鼠视网膜新生血管形成。在目的3中，一种良好表征的Scg3中和单克隆抗体，高治疗功效和安全性将被人源化，并分析其减轻DR泄漏的活性，病理性视网膜新生血管据我们所知，Scg 3是第一个高度选择性的血管生成因子。对Scg 3及其致病机制的研究将有助于发现和鉴定其他的具有相似疾病选择性的配体。抗Scg3抗体的人源化可能导致抗Scg3抗体的开发。新一类的“选择性血管生成阻断剂”，用于治疗DR和其他视网膜血管疾病。