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）：糖尿病性视网膜病（DR）是一种缺血性视网膜病，也被描述为炎症性疾病。 DR和其他缺血性视网膜病通过血液 - 视网膜屏障（BRB）分解和视网膜新生血管形成（NV）引起明显的视觉丧失。已经鉴定出许多与缺血和/或促炎性相关的分子，与DR的发病机理有关。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（PIGF）和肿瘤坏死因子A（TNFA）。 VEGF，PIGF和TNFA具有血管生成，VEGF和TNFA也是促炎性的。 VEGF已被确定为介导缺血性视网膜病的不良反应的关键分子，例如DR，早产性视网膜病变，分支和中央视网膜静脉闭塞，但PIGF和TNFA已被证明可以增强VEGFF VEGF的血管生成和血管生成性和血管生成性活性。通过使用TNFA敲除小鼠和通过不同信号通路作战的多种拮抗剂，这些分子在缺血性视网膜病变的发病机理中的作用和所涉及的途径可以得到确定。中断适当的信号通路可能会阻碍DR和其他缺血性视网膜病变和VEGF受体的拮抗剂的发展。将评估TNFA，PIGF和PKC的这种潜力。多种分子与DR和其他缺血性视网膜病有关，但是由于DR的复杂性，靶向单个分子的不可能有效地抑制BRB分解导致黄斑水肿。如果确定对DR的不良影响至关重要的分子和途径，则可以用作其治疗的靶标。如果确定了多个靶标分子，则可以设计组合疗法以提供最大的治疗有效性，同时最大程度地减少不良反应。