Role of PDLIM1 in Retinal Vascular Leakage and Proliferation

摘要 早产儿视网膜病变(ROP)是低出生体重儿的一种潜在致盲情况 这每年影响到全球5万多名儿童。ROP的发病率呈上升趋势，主要原因是 促进发展中国家新生儿护理的改善。ROP的基本病理生理机制是 外周视网膜缺血的后果。脑缺血可导致局部异常新生血管。 血管化和非血管化视网膜之间的边界。这些船只不称职，可能 导致水肿、出血、纤维化，并最终发展为牵引性视网膜脱离和 失明。重要的是，平行的血管变化也是其他患者视力障碍的原因 视网膜血管疾病，包括影响2580万人的糖尿病视网膜病变 这是导致劳动年龄人口失明的主要原因。函数中的更改 视网膜血管内皮细胞，包括新生血管和血管渗漏，是 疾病表型，但对这些细胞中发生的分子变化却知之甚少 他们的功能障碍。为了研究这些分子变化，我们提纯了血管内皮细胞 氧诱导视网膜病变(OIR)小鼠缺血模型中关键时间点的细胞 血管病变，并对转录组进行评估。这些数据表明PDLIM1是一种 在血管内皮细胞渗漏和增殖时特异性上调。在组织中 培养时，PDLIM1的表达会导致屏障性能的降低。我们现在已经产生了 PDLIM1基因敲除和过表达小鼠品系，并建议测试PDLIM1在视网膜中的作用 血管通透性和增殖性。这项工作可能确定PDLIM1作为一种新的治疗靶点 预防视网膜疾病中血-视网膜屏障的破坏和异常新生血管 脉管系统。

Abstract Retinopathy of Prematurity (ROP) is a potentially blinding condition of low birth weight premature children that affects over 50,000 children worldwide each year. The incidence of ROP is on the rise, primarily due to improvements in neonatal care in developing nations. The underlying pathophysiology of ROP is a consequence of ischemia of the peripheral retina. Ischemia can lead aberrant neovascularization at the border between the vascularized and non-vascularized retina. These vessels are incompetent and may lead to edema, bleeding, fibrosis, and can ultimately progress to a tractional retinal detachment and blindness. Importantly, parallel vascular changes are also responsible for visual morbidity in other diseases of the retinal vasculature, including diabetic retinopathy (DR), which affects 25.8 million Americans and is the leading cause of blindness in the working-age population. Changes in the function of the retinal vascular endothelial cells, including neovascularization and vascular leakage, are central to the disease phenotype, yet little is known about the molecular changes that occur in these cells that lead to their dysfunction. To investigate these molecular changes, we have purified the vascular endothelial cells during key timepoints in oxygen induced retinopathy (OIR), a mouse model of ischemic vasculopathy, and evaluated the transcriptome. These data identified PDLIM1 as a molecule that is upregulated specifically in the vascular endothelial cells at the time of leakage and proliferation. In tissue culture, expression of PDLIM1 results in a reduction of the barrier properties. We have now generated PDLIM1 knockout and overexpression mouse strains, and propose to test the role of PDLIM1 in retinal vascular permeability and proliferation. This work may identify PDLIM1 as a novel therapeutic target to prevent breakdown of the blood-retinal barrier and aberrant neovascularization in diseases of the retinal vasculature.