A Diabetic Retinopathy-Associated Vascular Permeability Factor

糖尿病视网膜病变相关血管通透性因子

• 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
• 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

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)是导致视力丧失的主要原因，全世界有近1亿人受到影响。 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 糖尿病黄斑水肿(DME)和增殖性糖尿病视网膜病变(PDR)。血管内皮细胞 生长因子(VEGF)抑制剂已被批准用于DME，但尚未被批准用于PDR，治疗效果有限。 识别更多的病理配体可能会导致开发新的治疗DME和PDR的方法。 我们最近发现分泌颗粒素III(Scg3)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生成，而不是正常血管。相反，血管内皮生长因子结合了 并诱导糖尿病血管和正常血管的血管生成。在数千个量化的内皮细胞中 与对照组相比，Scg3与糖尿病视网膜血管的结合活性最高，但与糖尿病视网膜血管的结合活性最低 正常的血管系统。然而，与PDR中的VEGF上调不同，Scg3的表达在 糖尿病视网膜。本课题旨在探讨Scg3基因表达上调的新致病机制。 选择性地与病变血管结合，而不是配体表达本身，加剧了DR的发病。在目标1中， 我们将量化和关联Scg3疾病相关的内皮结合活性与DR渗漏的严重程度。在……里面 目的2、建立Scg3内皮结合活性与病理严重程度的相关性。 小鼠视网膜新生血管。在目标3中，一种具有良好特性的Scg3中和单抗 高疗效和安全性将人性化，并分析其活性，以减轻DR渗漏和 病理性视网膜新生血管。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发现和鉴定其他 具有相似疾病选择性的配体。抗Scg3抗体的人源化可能导致一种 新型选择性血管生成阻滞剂，用于治疗DR和其他视网膜血管疾病。