The roles of Frizzled-4 and Sox17 in retinal vascular development and maintenance

Frizzled-4 和 Sox17 在视网膜血管发育和维护中的作用

• 批准号: 8597438
• 负责人: Max Tischfield
• 金额: $ 5.7万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597438
• 关键词: Actins; Adult; Alleles; Blindness; Blood Vessels; Cell physiology; Cytoskeleton; Development; Disease; Endothelial Cells; Fellowship; Future; Gene Silencing; Genetic Recombination; Goals; Growth; Health; Human; Inherited; Label; Laboratories; Lasers; Ligands; Maintenance; Mediating; Medical; Mus; Neuroglia; Pathway interactions; Pattern; Public Health; Reporting; Retina; Retinal; Retinal Diseases; Retinal Vein Occlusion; Role; Series; Signal Pathway; Signal Transduction; System; Testing; Time; Training; United States; Vascular Diseases; Work; base; central retinal artery; human FZD4 protein; in vivo; innovation; insight; medical schools; migration; neovascularization; paracrine; receptor; response; retina blood vessel structure; retina circulation disorder; retinal angiogenesis; transcription factor

DESCRIPTION (provided by applicant): Project Summary: Inherited and acquired retinal vascular disorders are a leading cause of blindness in the United States. The laboratory of Dr. Jeremy Nathans at Johns Hopkins Medical School has defined and characterized one of the central signaling systems that regulates vascular development in the vertebrate retina-the activation of the endothelial cell receptor Frizzled4 (Fz4) and coreceptor Lrp5 by the paracrine action of the Muller glia-derived ligand Norrin-and described how perturbations in this pathway cause a series of inherited retinal vascular disorders in humans. Recent findings from our lab now indicate that Fz4 is a pan-endothelial receptor that continues to be expressed in the mature retinal blood vessels of adult mice, suggesting that Fz4 functions may be required for the maintenance of mature blood vessels or how they respond to ischemic retinopathy. Also, we have identified a transcription factor, Sox17, which appears to be a downstream effector of Norrin/Fz4 signaling in the developing retinal vasculature. This training fellowship consists of two aims, the first of which proposes to characterize the in vivo functions of Fz4 in mature retinal blood vessels using conditional Fz4 mice that permit the manipulation of Fz4 signaling only after the adult vascular plexus has fully developed. Using these mice, we will also investigate the functions of Fz4 in ischemic retinopathy by characterizing the pattern and time course of new blood vessel growth in response to laser-induced retinal artery and vein occlusion. The second aim proposes to characterize the in vivo functions of Sox17 in retinal vascular development using conditionally targeted Sox17 mice that permit gene inactivation, via Cre-mediated recombination, specifically in endothelial cells. To help facilitate these studies, we are generating mouse lines that will enable us to fluorescently label the actin cytoskeleton and specific subpopulations of retinal endothelial cells. Together, these aims will provide important insight into the functions of the Norrin/Fz4 signaling pathway in vascular health, with the long term goals of developing innovative medical treatments for congenital and acquired retinal vascular disorders.

项目概述：遗传性和获得性视网膜血管疾病是美国致盲的主要原因。约翰霍普金斯医学院的Jeremy nathan博士的实验室定义并描述了调节脊椎动物视网膜血管发育的一个中枢信号系统——内皮细胞受体frzzled4 （Fz4）和辅助受体Lrp5通过Muller神经胶质衍生配体norrin的旁分泌作用被激活——并描述了这一途径的扰动如何导致人类一系列遗传性视网膜血管疾病。我们实验室最近的研究结果表明，Fz4是一种泛内皮受体，在成年小鼠的成熟视网膜血管中继续表达，这表明Fz4的功能可能是维持成熟血管或它们如何应对缺血性视网膜病变所必需的。此外，我们已经确定了一种转录因子Sox17，它似乎是发育中的视网膜血管中Norrin/Fz4信号的下游效应因子。这项研究包括两个目的，第一个目的是利用条件Fz4小鼠来表征成熟视网膜血管中Fz4的体内功能，条件Fz4小鼠只有在成年血管丛完全发育后才能操纵Fz4信号。利用这些小鼠，我们还将通过表征激光诱导视网膜动静脉闭塞后新血管生长的模式和时间过程来研究Fz4在缺血性视网膜病变中的功能。第二个目的是通过cre介导的重组，特别是在内皮细胞中，利用有条件靶向Sox17小鼠进行基因失活，表征Sox17在视网膜血管发育中的体内功能。为了促进这些研究，我们正在生成小鼠细胞系，使我们能够荧光标记肌动蛋白细胞骨架和视网膜内皮细胞的特定亚群。总之，这些目标将为Norrin/Fz4信号通路在血管健康中的功能提供重要的见解，并为先天性和获得性视网膜血管疾病开发创新的医学治疗方法。