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

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剂)如何在眼发育过程中发挥重要作用,以预防严重的发育性眼病。 在哺乳动物眼睛发育过程中,玻璃体血管系统(HVS)为发育中的眼睛提供营养,然后完全内卷。失败的HVS退化是被称为持久性增生性原始玻璃体(PHPV)的人类眼病的组成部分,其特征在于玻璃体中的晶状体后纤维血管组织、伴有白内障形成的透镜变性以及视网膜脱离和发育不良。调节HVS消退的分子机制和PHPV的病因在很大程度上是未知的。然而,偶尔有家族性PHPV的临床报告表明,它可能有遗传基础。 最近,我们意外地发现了Arf肿瘤抑制基因对小鼠眼睛的正常发育是必不可少的。具体而言,HVS未能渐开线和眼睛异常,密切模仿PHPV的发展在生命的第一周在Arf缺陷小鼠。小鼠眼发育过程中Arf表达的模式和时间表明,它可能在促进HVS消退中发挥主要作用。Arf基因产物在眼睛发育过程中的功能似乎与其已知的“下游”遗传靶点p53无关。这些发现提供了第一个证据,Arf调节眼睛发育,Arf可能是HVS消退的重要介质,以防止PHPV样眼病。 我们将在体外研究中的Arf-/-小鼠和新的基因工程小鼠品系的体内研究,以阐明Arf促进正常的HVS退化的机制,在发展中的眼睛。具体而言,我们的实验将(1)确定和表征胚胎和出生后眼睛中的Arf表达细胞;(2)确定它是否以细胞自主方式促进正常眼睛发育;(3)阐明Arf对玻璃体成熟和HVS退化所需的细胞和分子效应。我们实验的成功完成将为驱动眼睛中HVS消退的细胞和分子机制提供新的见解。这将增加我们对Arf功能的了解,并开始阐明PHPV和其他潜在血管性眼病的分子发病机制。

项目成果

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STEPHEN X SKAPEK其他文献

STEPHEN X SKAPEK的其他文献

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{{ truncateString('STEPHEN X SKAPEK', 18)}}的其他基金

Nominating vulnerabilities in fusion oncoprotein-driven rhabdomyosarcoma
提名融合癌蛋白驱动的横纹肌肉瘤的脆弱性
  • 批准号:
    10642101
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Identifying neuroblastoma drivers and bringing them to the clinic
识别神经母细胞瘤驱动因素并将其带到诊所
  • 批准号:
    10197505
  • 财政年份:
    2021
  • 资助金额:
    $ 30万
  • 项目类别:
Project 2: Targeted Therapies for Malignant Peripheral Nerve Sheath Tumors
项目2:恶性周围神经鞘瘤的靶向治疗
  • 批准号:
    8932163
  • 财政年份:
    2015
  • 资助金额:
    $ 30万
  • 项目类别:
Development and Cancer Scientific Program
发展与癌症科学计划
  • 批准号:
    10260731
  • 财政年份:
    2010
  • 资助金额:
    $ 30万
  • 项目类别:
Development and Cancer Program
发展和癌症计划
  • 批准号:
    10477964
  • 财政年份:
    2010
  • 资助金额:
    $ 30万
  • 项目类别:
Development and Cancer Program
发展与癌症计划
  • 批准号:
    10170614
  • 财政年份:
    2010
  • 资助金额:
    $ 30万
  • 项目类别:
Tgf 2-2 controls p19Arf during eye development
Tgf 2-2 在眼睛发育过程中控制 p19Arf
  • 批准号:
    7994803
  • 财政年份:
    2009
  • 资助金额:
    $ 30万
  • 项目类别:
Tgf 2-2 controls p19Arf during eye development
Tgf 2-2 在眼睛发育过程中控制 p19Arf
  • 批准号:
    7769253
  • 财政年份:
    2009
  • 资助金额:
    $ 30万
  • 项目类别:
Translation of Predictive Cancer Biomarkers into Clinical Practice
将预测性癌症生物标志物转化为临床实践
  • 批准号:
    7855461
  • 财政年份:
    2009
  • 资助金额:
    $ 30万
  • 项目类别:
Physician Scientist Oncology Training Program
医师科学家肿瘤学培训计划
  • 批准号:
    8931904
  • 财政年份:
    2009
  • 资助金额:
    $ 30万
  • 项目类别:

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接受血管生成抑制剂的癌症患者的心脏毒性评估和心脏毒性分子机制的阐明
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血管生成抑制剂双重治疗的体内微创疗效评价
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ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
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