Regulation of pericytes by Angiopoietin2-studies in new animal models

血管生成素2对周细胞的调节——新动物模型中的研究

• 批准号: 5347244
• 负责人: Professor Dr. Hans-Peter Hammes
• 金额: --
• 依托单位: V. Medizinische Klinik: Nephrologie, Endokrinologie, Diabetologie, Rheumatologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2001
• 资助国家: 德国
• 起止时间: 2000-12-31 至 2005-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5347244?language=en
• 关键词: Regulation; pericytes; Angiopoietin2; studies; new

Retinopathy is the most prevalent microvascular complication in diabetes. The earliest indication of hyperglycemia-induced retinal capillary damage is the loss of pericytes. Pericyte recruitment as an important part of vessel maturation involves several ligand-receptor systems including the Angiopoietin-Tie system. Tie2 mediates the dual effects of its two ligands angiopoietin 1 and 2, in which angiopoietin 1 (Ang 1) activates Tie2 while angiopoietin 2 (Ang 2) appears to be a natural antagonist of angiopoietin-1. For a better understanding and a possible basis for future interventions, we propose to establish and characterize a transgenic mouse which overexpresses Ang 2 under control of the photoreceptor opsin promoter in which pericyte recruitment, retinal capillary remodelling, and vascular regression is studied during postnatal development, in diabetes, and during hypoxia-induced proliferative retinopathy. This transgenic mouse line will be crossbred to a transgenic line which expresses the reporter gene LacZ under a pericytespecific promoter. This model enables to study pericyte modulation by Ang 2. Using a third transgenic mouse which expresses LacZ under the Ang 2 promoter, we will study the functional role of Ang2 in early diabetic pericyte loss. Ang 2 expression is modifiable by a variety of approaches, including Angiotensin receptor inhibition, inhibition of HB-EGF activation, EGF-receptor modulation and by reactive oxygen species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 expression and pericyte recruitment in early diabetes as markers. In summery, we will combine retinal analysis in development, and in diabetic and proliferative retinopathy with new transgenic mouse models whose common denominator is the modulation of Ang 2.

视网膜病变是糖尿病最常见的微血管并发症。高血糖诱导的视网膜毛细血管损伤的最早指征是周细胞的损失。周细胞募集作为血管成熟的重要组成部分涉及几个配体-受体系统，包括血管生成素-Tie系统。Tie 2介导其两个配体血管生成素1和2的双重作用，其中血管生成素1（Ang 1）激活Tie 2，而血管生成素2（Ang 2）似乎是血管生成素1的天然拮抗剂。为了更好地了解和未来的干预措施的可能基础，我们建议建立和表征转基因小鼠，过度表达血管紧张素2的感光视蛋白启动子的控制下，周细胞招聘，视网膜毛细血管重塑，血管退化的研究在出生后的发展，糖尿病，和缺氧诱导的增殖性视网膜病变。将该转基因小鼠系与在周细胞特异性启动子下表达报告基因LacZ的转基因系杂交。该模型能够研究血管紧张素2对周细胞的调节。使用第三个转基因小鼠表达LacZ下的血管生成素2启动子，我们将研究血管生成素2在早期糖尿病周细胞损失的功能作用。Ang 2的表达可通过多种途径调节，包括血管紧张素受体抑制、HB-EGF活化抑制、EGF受体调节和活性氧。将在使用Ang 2物质的体内模型中测试Ang 2修饰剂的这些靶点。将在体内模型中使用早期糖尿病中的Ang 2表达和周细胞募集作为标记物来测试Ang 2修饰剂的这些靶点。总之，我们将结合联合收割机视网膜分析在发展中，糖尿病和增殖性视网膜病变与新的转基因小鼠模型，其共同点是调节血管紧张素2。