CYP1B1 and Retinopathy of Prematurity

CYP1B1 和早产儿视网膜病变

基本信息

批准号：
7649188
负责人：
NADER SHEIBANI
金额：
$ 35.06万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649188
关键词：
Acetylcysteine Address Affect Air Angiogenesis Inhibition Angiogenesis Inhibitors Antioxidants Aryl Hydrocarbon Receptor Blood Vessels Blood capillaries CYP1B1 gene Capillary Endothelial Cell Cardiovascular system Cells Characteristics Cytochromes Data Development Diabetic Retinopathy Disease Embryo Embryonic Development Endothelial Cells Endothelium Excision Exhibits Eye Eye diseases Family Gene Targeting Genes Glaucoma Homeostasis Human In Vitro Irido-corneo-trabecular dysgenesis Isoprostanes Link Macular degeneration Mediating Messenger RNA Metabolism Mitochondria Molecular Morphogenesis Mus Mutation NADPH Oxidase Neural Crest Open-Angle Glaucoma Oxidation-Reduction Oxidative Stress Oxygen Pathogenesis Phenotype Physiological Play Polyunsaturated Fatty Acids Premature Infant Process Proteins Reactive Oxygen Species Regulation Regulatory Pathway Research Retina Retinal Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Role Smooth Muscle Myocytes Source Structure of sinus venosus of sclera Testing Trabecular meshwork structure Vascular Endothelial Cell Vascularization Xanthine Oxidase angiogenesis anterior chamber atheroprotective attenuation capillary cell type density effective therapy hindbrain in vivo insight matrigel member neovascularization new growth novel retinal angiogenesis shear stress thrombospondin 2 transcription factor

项目摘要

The expression of specific cytochrome P450s (CYPs) in vascular smooth muscle cells and endothelial cells (EC). and the critical contribution of their products to vascular function suggest important roles for these genes in vascular homeostasis. Although lack of CYP1 B1 is shown to influence the function and development of the trabecular meshwork. Its physiological role in the development of retinal vasculature and angiogenesis has not been previously studied. Our preliminary data indicate that CYP1 B1 plays an essential role in retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy (aiR). The CYP1 B1-deficient (CYP1 B1-/-) mice exhibit reduced retinal vascular density and fail to neovascularize their retina during aiR. Furthermore. retinal EC prepared from CYP1B1-/- mice are less migratory and fail to undergo capillary morphogenesis in Matrigel. These cells also express increased amounts of thrombospondin-2 (TSP2). an endogenous inhibitor of angiogenesis whose expression is modulated by cellular oxidative stress. Our hypothesis is that CYP1 B1 plays a central role in maintaining the redox state of the endothelium in check, such that in its absence increased oxidative stress promotes sustained activation of NF-KB and TSP2 expression, and inhibits angiogenesis. We have now shown that changes in TSP2 expression mediate the effects of CYP1 B1-deficiency on retinal vascularization in vivo and capillary morphogenesis of retinal EC in culture. We have also shown increased oxidative state mediates these effects of CYP1B1-deficiency on retinal neovascularization during OIR and can be reversed in the presence of an antioxidant. In addition changes in CYP1 B 1 expression are sufficient to affect TSP2 expression and retinal EC capillary morphogenesis in vitro. Therefore these changes are modulated by the intracellular oxidative stress in a CYP1 B1 dependent manner. Here we will determine the source of reactive oxygen species and will delineate the potential regulatory role of redox sensitive transcription factors NF-KB in increased TSP2 expression. We will also determine whether expression of NF-KB is modulated by CYP1 B1 through removal of oxygenation products. Understanding how CYP1 B1 and its metabolites regulate retinal vascular homeostasis will provide insight into CYP1 B1 mechanisms of action and aid in the development of alternative ways to modulate retinal angiogenesis.

血管平滑肌细胞和内皮细胞（EC）中特异性细胞色素P450（CYP）的表达。其产品对血管功能的关键贡献表明了这些基因在血管稳态中的重要作用。尽管缺乏CYP1 B1会影响小梁网的功能和发展。先前尚未研究其在视网膜脉管系统发展和血管生成中的生理作用。我们的初步数据表明，CYP1 B1在视网膜血管发育和氧诱导的缺血期间起着至关重要的作用视网膜病（空气）。 CYP1 B1缺陷型（CYP1 B1 - / - ）小鼠表现出降低的视网膜血管密度，并且在空气中未能使其视网膜新生。此外。由CYP1B1 - / - 小鼠制备的视网膜EC的迁移较少，并且无法在基质中进行毛细血管形态发生。这些细胞还表达了增加数量的血小板蛋白-2（TSP2）。血管生成的内源性抑制剂，其表达是由细胞氧化应激调节的。我们的假设是，CYP1 B1在控制内皮的氧化还原状态中起着核心作用，因此，在其缺失的情况下，氧化应激的增加促进了NF-KB和TSP2表达的持续激活，并抑制血管生成。现在我们已经表明，TSP2表达的变化介导了 CYP1 B1缺乏视网膜在体内和视网膜EC培养中的毛细血管形态发生的缺陷。我们还显示，增加的氧化态介导了CYP1B1缺陷对OIR期间视网膜新血管形成的影响，并且可以在存在抗氧化剂的情况下逆转。另外，CYP1 B 1表达的变化足以影响TSP2表达和视网膜EC毛细血管形态发生。因此，这些变化是通过CYP1 B1依赖性方式的细胞内氧化应激调节的。在这里，我们将确定活性氧的来源，并描述氧化还原敏感转录因子NF-KB在增加TSP2中的潜在调节作用表达。我们还将确定是否通过去除氧合产物来调节NF-KB的表达。了解CYP1 B1及其代谢物如何调节视网膜血管稳态将提供对CYP1 B1作用机理的见解，并有助于开发调节视网膜血管生成的替代方法。