Role of PDLIM1 in Retinal Vascular Leakage and Proliferation

PDLIM1 在视网膜血管渗漏和增殖中的作用

• 批准号: 9902472
• 负责人: Eric D Nudleman
• 金额: $ 23.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902472
• 关键词: Address; Affect; Age; American; Animals; Area; Blindness; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood-Retinal Barrier; Brain; Cell Culture Techniques; Cells; Child; Childhood; Colon Carcinoma; Control Animal; Data; Developing Countries; Development; Diabetic Retinopathy; Disease; Doxycycline; Edema; Endothelial Cells; Endothelium; Epilepsy; Exposure to; Extravasation; Fibrosis; Functional disorder; Gene Expression Profiling; Genes; Genetic Transcription; Growth; Hemorrhage; Hypoxia; Incidence; Intention; Ischemia; Knock-out; Knockout Mice; Lead; Low Birth Weight Infant; Luciferases; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Oxygen; Peripheral; Permeability; Phenotype; Proliferating; Property; Reporter; Retina; Retinal Detachment; Retinal Diseases; Retinopathy of Prematurity; Role; Seizures; Stroke; Survival Rate; System; Testing; Time; Traction; Transfection; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Up-Regulation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular Proliferation; Visual; WNT Signaling Pathway; Work; World Health Organization; aging population; beta catenin; blind; cytokine; disease phenotype; improved; in vivo; mouse model; neonatal care; neovascular; neovascularization; new therapeutic target; overexpression; premature; prevent; retina blood vessel structure; retinal angiogenesis; tissue culture; transcription factor; transcriptome

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.

摘要 早产儿视网膜病变（ROP）是低出生体重早产儿的潜在致盲性疾病 全世界每年有超过5万名儿童受到影响ROP的发病率正在上升，主要是由于 发展中国家新生儿护理的改善。ROP的潜在病理生理学是 周边视网膜缺血的结果。缺血可导致血管新生异常， 血管化和非血管化视网膜之间的边界。这些血管功能不全， 导致水肿、出血、纤维化，并可最终进展为牵引性视网膜脱离， 失明重要的是，平行的血管变化也是造成其他人视觉疾病的原因。 视网膜血管疾病，包括糖尿病视网膜病变（DR），影响2580万人 美国人，是工作年龄人口失明的主要原因。功能的变化 视网膜血管内皮细胞的增殖，包括新生血管形成和血管渗漏， 疾病表型，但很少有人知道这些细胞中发生的分子变化，导致 他们的功能障碍。为了研究这些分子变化，我们纯化了血管内皮细胞， 在氧诱导视网膜病变（OIR）的关键时间点，缺血性视网膜病变的小鼠模型 血管病变，并评估转录组。这些数据将PDLIM 1鉴定为一种分子， 在渗漏和增殖时在血管内皮细胞中特异性上调。组织中 在培养中，PDLIM 1的表达导致屏障性能的降低。我们现在已经生成了 PDLIM 1敲除和过表达小鼠品系，并提出测试PDLIM 1在视网膜病变中的作用。 血管通透性和增殖。这项工作可能将PDLIM 1确定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形成 脉管系统

项目成果

Microcornea, Posterior Megalolenticonus, Persistent Fetal Vasculature, and Coloboma Syndrome Associated With a New Mutation in ZNF408.

• DOI: 10.3928/23258160-20190401-10
• 发表时间: 2019-04
• 期刊: Ophthalmic surgery, lasers & imaging retina
• 作者: Geoffrey A. Weiner;E. Nudleman

IDENTIFICATION OF FACTORS RELATED TO SUBFOVEAL DETACHMENT SECONDARY TO EPIRETINAL MEMBRANE.

与视网膜前膜继发的凹下脱离相关的因素的识别。

• DOI: 10.1097/iae.0000000000002056
• 发表时间: 2019
• 期刊: Retina (Philadelphia, Pa.)
• 作者: Muftuoglu,IlkayKilic;Lin,Tiezhu;Nudleman,Eric;Gaber,Raouf;Bartsch,Dirk-Uwe;Freeman,WilliamR
• 通讯作者: Freeman,WilliamR