ARF Controls Vascular Regression During Eye Development

ARF 控制眼睛发育过程中的血管退化

• 批准号: 8391362
• 负责人: STEPHEN X SKAPEK
• 金额: $ 36.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391362
• 关键词: ARF; Controls; Vascular; Regression; During

DESCRIPTION (provided by applicant): The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I will specifically investigate the roles of Arf, an important mammalian tumor suppressor gene, and Platelet-derived growth factor receptor 2 (Pdgfr2), which contributes to a variety of developmental, physiological, and pathological processes. To assure normal development, mammalian cells have mechanisms to check cell proliferation stimuli and preserve cell cycle arrest. When gone awry, excess mitogenic signals lead to developmental defects and a wide variety of pathological processes. The Arf gene product, p19Arf, was initially discovered to play a key role as a "fuse" to control excess mitogens and prevent tumor formation. Work supported by the first cycle of this R01 has challenged this simple paradigm as I have shown p19Arf plays an essential function during mouse eye development. Without it, excess numbers of perivascular cells envelop the hyaloid vasculature in the vitreous, preventing their normal involution during the later stages of eye development. Mice lacking Arf are blind due to a pathological process strikingly similar to severe persistent hyperplastic primary vitreous (PHPV). We have identified a new biochemical and genetic pathway in which the Arf gene product blocks signals stemming from Pdgfr2 to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. In the current proposal, I will tackle the critical questions that still cloud our understanding of the functional relationship between the two gene products. I will take advantage of existing cell culture system and mouse models one of which will be developed in this proposal to (1) identify how p19Arf- dependent control of Pdgfr2 influences eye development; (2) uncover mechanisms by with Pdgfr2 fosters vitreous hyperplasia without Arf; and (3) elucidate mechanisms by which Arf represses Pdgfr2 expression. Insight into how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals will address fundamental aspects of eye development; leave me ideally positioned to address whether genetic abnormalities in this new "pathway" contribute to the pathogenesis of PHPV or other vitreoretinopathies; and begin to investigate whether pharmacological disruption of Pdgfr2 signaling can ameliorate the disease. PUBLIC HEALTH RELEVANCE: The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I have identified a new biochemical and genetic pathway in which the Arf gene product, p19Arf, blocks signals stemming from Platelet-derived growth factor receptor 2 (Pdgfr2) to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. I will use cell culture-based and mouse models to uncover how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals.

描述（由申请人提供）：本提案的主要目标是了解在眼睛发育过程中预防原发性玻璃体增生和指导玻璃体血管系统（HVS）退化的分子事件。我将特别研究重要的哺乳动物肿瘤抑制基因Arf和血小板衍生生长因子受体2 （Pdgfr2）的作用，Pdgfr2参与多种发育、生理和病理过程。为了保证正常发育，哺乳动物细胞具有抑制细胞增殖刺激和维持细胞周期阻滞的机制。当出错时，过量的有丝分裂信号会导致发育缺陷和各种各样的病理过程。Arf基因产物p19Arf最初被发现在控制过量有丝分裂原和防止肿瘤形成方面发挥着“融合”的关键作用。这个R01的第一个周期支持的工作挑战了这个简单的范式，因为我已经证明p19Arf在小鼠眼睛发育过程中起着重要的作用。没有它，过多的血管周围细胞会包围玻璃体中的玻璃状血管，阻止它们在眼睛发育后期的正常复旧。缺乏Arf的小鼠由于与严重持续性增殖性原发性玻璃体（PHPV）惊人相似的病理过程而失明。我们已经确定了一种新的生化和遗传途径，其中Arf基因产物阻断来自Pdgfr2的信号，可能通过抑制受体的表达来预防原发性玻璃体增生。在目前的建议中，我将解决仍然模糊我们对两个基因产物之间的功能关系的理解的关键问题。我将利用现有的细胞培养系统和小鼠模型，其中一个将在本提案中开发：(1)确定p19Arf依赖的Pdgfr2控制如何影响眼睛发育；(2)揭示Pdgfr2在无Arf的情况下促进玻璃体增生的机制；(3)阐明Arf抑制Pdgfr2表达的机制。了解Pdgfr2如何在缺乏Arf的情况下促进眼睛病理，以及p19Arf如何控制Pdgfr2依赖的信号，将解决眼睛发育的基本问题；这一新的“途径”中的基因异常是否导致了PHPV或其他玻璃体视网膜病变的发病机制？并开始研究Pdgfr2信号的药理破坏是否可以改善疾病。公共卫生相关性：本提案的主要目标是了解预防原发性玻璃体增生的分子事件，并指导眼睛发育过程中玻璃体血管系统（HVS）的退化。我已经确定了一种新的生化和遗传途径，其中Arf基因产物p19Arf可能通过抑制受体的表达来阻断来自血小板衍生生长因子受体2 （Pdgfr2）的信号，以防止原发性玻璃体增生。我将使用基于细胞培养和小鼠模型来揭示Pdgfr2如何在缺乏Arf的情况下促进眼部病理，以及p19Arf如何控制Pdgfr2依赖的信号。