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: 8251644
• 负责人: Max Tischfield
• 金额: $ 5.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/8251644
• 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; Mediator of activation protein; Medical; Mus; Mutant Strains Mice; Neuroglia; Pathway interactions; Pattern; Public Health; Reporting; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Retinal Vein Occlusion; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; Time; Training; United States; Vascular Diseases; Work; base; central retinal artery; human FZD4 protein; in vivo; innovation; insight; loss of function; medical schools; migration; neovascularization; paracrine; receptor; response; retina blood vessel structure; retina circulation disorder; retinal angiogenesis; transcription factor

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.

项目摘要： 遗传和获得的残留血管疾病是美国失明的主要原因。约翰·霍普金斯医学院（Johns Hopkins Medical School）的杰里米·内森（Jeremy Nathans）博士的实验室定义并描述了一种中心信号系统之一，该系统调节脊椎动物视网膜中的血管发育，而脊椎动物受体受体脱毛4（fz4）的激活和coreceptor lrp5的激活和coreceptor lrp5的paroctiation rrp5均通过这种遗传的ligand norrin norrin norrin norrin norrin norrin norrin norrin norrin？人类的视网膜血管疾病。我们实验室的最新发现现在表明FZ4是一种泛皮受体，在成年小鼠的成熟残留血管中继续表达，这表明可能需要FZ4功能来维持成熟的血管或它们对缺血性视网膜病的反应。另外，我们已经确定了转录因子SOX17，该训练研究金由两个目标组成，其中第一个提案是表征FZ4在成熟视网膜血管中FZ4的体内功能，仅使用有条件的FZ4小鼠使用有条件的FZ4小鼠，该小鼠仅在成年血管Plexus后才开发FZ4信号。使用这些小鼠，我们还将通过表征对激光引起的视网膜动脉和静脉闭塞的新血管生长的模式和时间过程来研究FZ4在缺血性视网膜病中的功能。第二个目标是使用有条件的靶向Sox17小鼠在视网膜血管发育中表征Sox17的体内功能，该小鼠通过CRE介导的重组，特别是在内皮细胞中允许基因失活的小鼠。为了帮助支持这些研究，我们正在生成小鼠线，使我们能够荧光标记肌动蛋白细胞骨架和残留内皮细胞的特定亚群。这些目标共同将对Norrin/FZ4信号通路在血管健康中的功能提供重要的见解，其长期目标是为先天性和获得的残留血管疾病开发创新的医疗治疗。