Pathogenesis of choroidal neovascularization

脉络膜新生血管的发病机制

基本信息

批准号：
7514510
负责人：
RONG WEN
金额：
$ 2.53万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7514510
关键词：
angiogenesis choroid uvea confocal scanning microscopy extracellular matrix fluorescence microscopy growth inhibitors immunocytochemistry in situ hybridization laboratory rat macular degeneration neutralizing antibody pathologic process retina circulation sirolimus vascular endothelial growth factors

项目摘要

DESCRIPTION (provided by applicant): The long-term objectives are to understand the pathogenesis of CNV (choroidal neovascularization) in AMD (age-related macular degeneration) and to search for suitable treatments. AMD is the leading cause of blindness in the population over 65 years old. Exudative AMD, characterized by CNV, causes severe loss of vision. Options of treatments are limited for those with exudative AMD. Development of new treatments is hindered by the poor understanding of pathogenesis of CNV in AMD, and the lack of suitable animal models. As the senior population continues to expand rapidly, the situation is reaching epidemic proportions. This proposal focuses on the pathogenesis of CNV. Four Specific Aims are proposed to study the roles of ECM (extracellular matrix) deposits, VEGF (vascular endothelial growth factor), and mTOR (mammalian target of rapamycin) in CNV development. Abnormal ECM deposits are commonly found in AMD with CNV, but their roles in CNV development are not clear. Several new techniques will be used to create artificial ECM deposits in the subretinal space of experimental rats, to induce CNV, and to visualize blood vessels. The first Specific Aim will attempt to establish a causal relation between ECM deposits and CNV. New blood vessels induced by ECM deposits from the choroid will be identified, which would support the causal relation. Positive results have been observed in preliminary studies. The second will test a hypothesis that the space and microenvironment provided by ECM deposits facilitate the spread of CNV. Subretinal deposits will be created using ECM and non-ECM materials. Degrees of CNV in samples will be measured as a CNV indexes and digital CNV volume. Significantly higher CNV indexes or volume in ECM deposits would support the hypothesis. The third Specific Aim will test a hypothesis that VEGF is essential for CNV development. Two VEGF inhibitors, a soluble VEGFR-1 and a VEGF antibody, will be used to block the interaction between VEGF and its receptors. Positive results should confirm the role of VEGF in CNV. The last Specific Aim will attempt to establish a role of mTOR in CNV development; mTOR inhibitor rapamycin will be used. Complete inhibition of CNV by rapamycin has been observed in preliminary studies. Data from these experiments would not only shed light on the roles of ECM deposits, VEGF, and mTOR in CNV pathogenesis, but also provide basis for developing new strategies to control CNV in AMD.

描述（由申请人提供）：长期目标是了解AMD（与年龄相关的黄斑变性）中CNV（脉络膜新生血管形成）的发病机理，并寻找合适的治疗方法。 AMD是65岁以上人口失明的主要原因。以CNV为特征的渗出性AMD会导致严重的视力丧失。对于渗出性AMD的人的治疗方法受到限制。由于对AMD中CNV的发病机理的不良理解以及缺乏合适的动物模型，因此阻碍了新处理的发展。随着老年人的继续迅速扩大，这种情况正在达到流行病的比例。该提案的重点是CNV的发病机理。提出了四个具体目的，以研究ECM（细胞外基质）沉积物，VEGF（血管内皮生长因子）和MTOR（雷帕霉素的哺乳动物靶标）在CNV发育中的作用。 ECM沉积物异常在具有CNV的AMD中发现，但它们在CNV发育中的作用尚不清楚。几种新技术将用于在实验大鼠的视网膜下空间中创建人工ECM沉积物，以诱导CNV并可视化血管。第一个具体目标将尝试在ECM存款与CNV之间建立因果关系。将确定由脉络膜ECM沉积物引起的新血管，这将支持因果关系。在初步研究中已经观察到了积极的结果。第二个将检验一个假设，即ECM沉积提供的空间和微环境有助于CNV的扩散。视网膜下沉积将使用ECM和非ECM材料创建。样品中的CNV度将作为CNV索引和数字CNV体积测量。 ECM沉积中的CNV指数或体积明显更高，将支持该假设。第三个特定目的将检验一个假设，即VEGF对于CNV开发至关重要。两种可溶性VEGFR-1和VEGF抗体的VEGF抑制剂将用于阻断VEGF及其受体之间的相互作用。积极的结果应确认VEGF在CNV中的作用。最后的特定目标将试图确立MTOR在CNV开发中的作用。将使用MTOR抑制剂雷帕霉素。在初步研究中已经观察到了雷帕霉素对CNV的完全抑制作用。这些实验的数据不仅会阐明ECM沉积物，VEGF和MTOR在CNV发病机理中的作用，而且还为制定了控制AMD中CNV的新策略提供了基础。