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Potential target molecules for ischemic retinopathies

缺血性视网膜病的潜在靶分子

基本信息

批准号：
8126322
负责人：
Gerard Anthony Lutty
金额：
$ 35.07万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is an ischemic retinopathy, which has also been described as an inflammatory disorder. DR and other ischemic retinopathies cause significant visual loss through blood-retinal barrier (BRB) breakdown and retinal neovascularization (NV). A number of molecules have been identified that are associated with ischemia and/or are pro-inflammatory and are implicated with the pathogenesis of DR. These molecules include vascular endothelial growth factor (VEGF) and its receptors, placental growth factor (PIGF), and tumor necrosis factor-a (TNFa). VEGF, PIGF, and TNFa are angiogenic and VEGF and TNFa are also pro-inflammatory. VEGF has been identified as a key molecule in mediating the adverse effects of ischemic retinopathies such as DR, retinopathy of prematurity, and branch and central retinal vein occlusions, but PIGF and TNFa have been shown to potentiate the angiogenic and vasopermeability activities of VEGF. Through the use of TNFa knockout mice and a variety of antagonists that operate through different signaling pathways, the roles of these molecules in the pathogenesis of ischemic retinopathies and the pathways involved may be determined. Interrupting the appropriate signaling pathway could impede the progression of DR and other ischemic retinopathies and antagonists of VEGF receptors. TNFa, PIGF, and PKC will be evaluated for this potential. A variety of molecules are associated with DR and other ischemic retinopathies, but due to the complexity of DR, it is unlikely that targeting a single molecule will effectively inhibit BRB breakdown leading to macular edema. If the molecules and pathways that are critical for the adverse effects of DR to develop are identified, they can be used as targets for its treatment. If multiple target molecules are identified, combination therapies can be devised to provide maximum therapeutic effectiveness while minimizing adverse effects.

描述（由申请人提供）：糖尿病视网膜病变（DR）是一种缺血性视网膜病变，也被描述为一种炎症性疾病。DR和其他缺血性视网膜病通过血-视网膜屏障（BRB）破坏和视网膜新生血管（NV）引起显著的视力丧失。已经鉴定了许多与缺血相关和/或促炎的分子，并且这些分子与DR的发病机制有关。这些分子包括血管内皮生长因子（VEGF）及其受体、胎盘生长因子（PlGF）和肿瘤坏死因子-α（TNF α）。VEGF、PlGF和TNFa是血管生成的，并且VEGF和TNFa也是促炎的。VEGF已被鉴定为介导缺血性视网膜病如DR、早产儿视网膜病和视网膜分支和中央静脉阻塞的不良作用的关键分子，但PIGF和TNF α已显示增强VEGF的血管生成和血管渗透性活性。通过使用TNFa敲除小鼠和通过不同信号传导途径起作用的多种拮抗剂，可以确定这些分子在缺血性视网膜病发病机制中的作用和所涉及的途径。阻断适当的信号传导通路可以阻止DR和其他缺血性视网膜病变的进展，以及VEGF受体的拮抗剂。将评估TNFa、PlGF和PKC的这种潜力。多种分子与DR和其他缺血性视网膜病相关，但由于DR的复杂性，靶向单一分子不太可能有效抑制导致黄斑水肿的BRB分解。如果确定了对DR不良反应发展至关重要的分子和途径，它们可以用作治疗的靶点。如果鉴定出多个靶分子，则可以设计组合疗法以提供最大的治疗效果，同时最小化副作用。