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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.

细胞色素P450在血管平滑肌细胞和内皮细胞中的表达。以及它们的产物对血管功能的重要贡献表明这些基因在血管稳态中的重要作用。虽然缺乏CYP 1B 1被证明会影响小梁网的功能和发育。其在视网膜血管系统和血管生成的发育中的生理作用以前没有被研究过。我们的初步数据表明，CYP 1 B1在氧诱导的缺血性视网膜病变的视网膜血管发育和新生血管形成中起重要作用。视网膜病变（aiR）。CYP 1B 1缺陷（CYP 1B 1-/-）小鼠在aiR期间表现出视网膜血管密度降低并且不能使其视网膜新生血管。此外。从CYP 1B 1-/-小鼠制备的视网膜EC迁移性较低，并且不能在基质胶中经历毛细血管形态发生。这些细胞还表达增加量的血小板反应蛋白-2（TSP 2）。一种内源性血管生成抑制剂，其表达受细胞氧化应激调节。我们的假设是，CYP 1B 1在维持内皮细胞的氧化还原状态中起核心作用，使得在其不存在的情况下，增加的氧化应激促进NF-κ B和TSP 2表达的持续活化，并抑制血管生成。我们现在已经表明，TSP 2表达的变化介导了 CYP 1 B1缺乏对体内视网膜血管形成和培养中视网膜EC的毛细血管形态发生的影响我们还发现，在OIR期间，氧化状态的增加介导了CYP 1B 1缺乏对视网膜新生血管的这些影响，并且在抗氧化剂的存在下可以逆转。此外，CYP 1 B 1表达的变化足以影响TSP 2表达和体外视网膜EC毛细血管形态发生。因此，这些变化是由细胞内氧化应激以CYP 1B 1依赖性方式调节的。在此，我们将确定活性氧的来源，并描述氧化还原敏感性转录因子NF-κ B在TSP 2增加中的潜在调节作用。表情我们还将确定NF-κ B的表达是否通过清除氧合产物被CYP 1B 1调节。了解CYP 1 B1及其代谢物如何调节视网膜血管稳态将提供对CYP 1 B1作用机制的深入了解，并有助于开发调节视网膜血管生成的替代方法。