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ARF controls vascular regression during eye development

ARF 控制眼睛发育过程中的血管退化

基本信息

批准号：
7281190
负责人：
STEPHEN X SKAPEK
金额：
$ 1.52万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7281190
关键词：
Address Age Angiogenic Factor Angiogenic Switch Appendix Automobile Driving Blindness Blood Vessels Cancer Biology Cataract Cells Clinical Cultured Cells Development Disease Disease regression Dysplasia Embryo Equilibrium Etiology Eye Eye Abnormalities Eye Development Eye diseases Future Genetic Genetically Engineered Mouse Goals Human Hyperplasia In Situ Hybridization In Vitro Knowledge LacZ Genes Lead Life Malignant Neoplasms Mediator of activation protein Modeling Molecular Mouse Strains Mus Numbers Nutrient Pathogenesis Pathologic Pathologic Processes Pattern Play Protein p53 Proteins Regulation Reporter Reporting Research Personnel Retinal Detachment Role Stream TP53 gene Therapeutic Time Tissues Tumor Suppressor Genes Tumor Suppressor Proteins Vascular System Week angiogenesis base blocking factor human disease in vivo insight lens postnatal prevent programs research study tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The major goal of this proposal is to determine how Arf, a potent tumor suppressor, plays an essential role during eye development to prevent a severe developmental eye disease. During mammalian eye development, the hyaloid vascular system (HVS) supplies nutrients to the developing eye and then completely involutes. Failed HVS regression is an integral component of a human eye disease known as persistent hyperplastic primary vitreous (PHPV), characterized by retrolental fibrovascular tissue in the vitreous, lens degeneration with cataract formation, and retinal detachment and dysplasia. Molecular mechanisms regulating HVS regression and the etiology of PHPV are largely unknown. However, occasional clinical reports of familial PHPV suggest that it may have a genetic basis. Recently, we have made the unexpected discovery that the Arf tumor suppressor gene is essential for the normal development of the mouse eye. Specifically, the HVS fails to involute and eye abnormalities that closely mimic PHPV develop in the first weeks of life in Arf-deficient mice. The pattern and timing of Arf expression during mouse eye development suggest that it may play a primary role in promoting HVS regression. The function of the Arf gene product during eye development appears to be independent of its known "down-stream" genetic target, p53. These findings provide the first evidence that Arf regulates eye development and that Arf may be an essential mediator of HVS regression to prevent a PHPV-like eye disease. We will couple in vivo studies of Arf-/- mice and new genetically-engineered mouse strains with in vitro studies to elucidate the mechanisms by which Arf promotes normal HVS regression in the developing eye. Specifically, our experiments will (1) identify and characterize the Arf-expressing cells in the embryonic and postnatal eye; (2) determine whether it acts in a cell-autonomous manner to promote normal eye development; and (3) elucidate the cellular and molecular effects of Arf that are required for vitreous maturation and HVS involution. The successful completion of our experiments will provide new insight into cellular and molecular mechanisms driving HVS regression in the eye. This should augment our knowledge of Arf function and begin to clarify the molecular pathogenesis for PHPV and potentially other vascular eye diseases.

描述（由申请人提供）：本提案的主要目标是确定Arf（一种有效的肿瘤抑制因子）如何在眼睛发育过程中发挥重要作用，以预防严重的发育性眼病。