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
• 负责人: STEPHEN X SKAPEK
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769253
• 关键词: Abnormal Cell; Anatomy; Applications Grants; Automobile Driving; Blood Vessels; Cell Culture Techniques; Cell Death; Cell Proliferation; Cells; Coupled; Cues; Data; Defect; Development; Developmental Process; Dysplasia; Embryo; Embryonic Development; Evaluation; Exploratory/Developmental Grant; Eye; Eye Development; Eye diseases; Failure; Genes; Genetic Transcription; Goals; Government; Human; Hyperplasia; In Vitro; Individual; Knowledge; Laboratories; Left; Lens Opacities; Light; Modeling; Molecular; Molecular Abnormality; Molecular Target; Mus; Nutrient; Oncogene Activation; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Pattern; Pericytes; Persons; Phenotype; Photoreceptors; Physiological Processes; Play; Positioning Attribute; Process; Proteins; Published Comment; Publishing; Research Proposals; Retina; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Syndrome; Transforming Growth Factors; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vascular System; Vision; Work; base; blind; cancer cell; human disease; in vivo; insight; interest; lens; member; mouse development; mouse model; p19ARF; prevent; promoter; public health relevance; research study; response; sensor; vascular bed; vessel regression

DESCRIPTION (provided by applicant): Although Arf is broadly known as a tumor suppressor gene, it also is essential for mouse eye development. Mice lacking Arf are born blind with a severe developmental eye disease, mimicking a human eye disease known as Persistent Hyperplastic Primary Vitreous. Very little is known about basic mechanisms that control Arf transcription or the expression of its gene product, p19Arf. One of my overall goals is to use elucidate the fundamental mechanisms driving the expression of this important gene. The existing dogma holds that Arf functions as an "oncogene sensor" such that its expression is induced in cells carrying abnormal or excessive proliferation signals from oncogene activation. Mechanisms by which an individual cell can discriminate between an oncogenic stimulus and an equally intense, normal proliferation signal - such as that occurring during development - are not at all clear. Recently, though, members of my laboratory and I made a surprising discovering challenging the current paradigm. Specifically, while exploring mechanisms by which p19Arf prevented primary vitreous hyperplasia in the developing mouse, we showed that its promoter is activated in an exquisitely controlled pattern during mouse development. This finding allows me to safely conclude that Arf control must extend beyond the cell intrinsic signals provided by oncogene activation. Working from our new findings that part of the Tgf22 -/- phenotype resembles that in the absence of Arf, I have established the Transforming Growth Factor 2-2 (Tgf22) as an essential regulator of p19Arf and that the latter is required for the anti-mitogenic effects of Tgf22 in vivo and in vitro. In this proposal, I will take advantage of existing mouse and cell culture models to close three critical gaps in my knowledge: Does Tgf2 directly control p19Arf expression during eye development? What are the essential intracellular signals emanating from Tgf22? What are the fundamental mechanisms acting at the Arf promoter? Studying this pathway from Tgf22 to p19Arf will deepen our understanding of how the two proteins operate in the developing eye, and better define the genetic abnormalities that can contribute to human diseases characterized by hyperplasia in the vitreous. From a broader perspective, though, this potentially sheds new light on how Arf may be controlled in cancer cells and how Tgf2s may carry out other functions during development. PUBLIC HEALTH RELEVANCE: The Arf gene plays an essential role to prevent primary vitreous hyperplasia and hyaloid vascular regression, processes that are critical for normal vision. We have previously defined its temporally- and spatially-restricted expression in the developing eye, but the mechanisms underlying this expression pattern are totally unknown. My Preliminary Studies in this proposal provide the first insight: Tgf22 plays a key role in the process. Experiments in this proposal define will define the cellular and molecular mechanisms by which Tgf22 accomplishes this.

描述（由申请人提供）：尽管ARF广泛称为肿瘤抑制基因，但它对于小鼠眼发发育也是必不可少的。缺乏ARF的小鼠天生是患有严重发育性眼病的盲人，模仿了一种被称为持续增生原代玻璃体的人眼病。关于控制ARF转录或其基因产物P19arf的表达的基本机制，知之甚少。我的总体目标之一是阐明推动这一重要基因表达的基本机制。现有的教条认为ARF充当“致癌基因传感器”，因此它的表达是在癌细胞激活中携带异常或过度增殖信号的细胞中诱导的。单个细胞可以区分致癌刺激和同样强烈的正常增殖信号的机制（例如在发育过程中发生的机制）尚不清楚。但是，最近，我和我的实验室成员令人惊讶地发现了当前范式的挑战。具体而言，在探索P19ARF阻止发育中的原代玻璃体增生的机制时，我们表明其启动子在小鼠发育过程中以精美的控制模式激活。这一发现使我可以安全地得出结论，ARF控制必须超出癌基因激活提供的细胞内在信号。从我们的新发现中工作，TGF22 - / - 表型的一部分类似于在没有ARF的情况下，我确定了转化的生长因子2-2（TGF22）作为P19ARF的必不可少的调节剂，而后者是TGF22 INVIVO的抗激发作用所必需的。在此提案中，我将利用现有的小鼠和细胞培养模型来缩小我所知的三个关键差距：TGF2是否直接控制眼睛发育过程中的P19ARF表达？ TGF22发出的必需细胞内信号是什么？在ARF启动子上作用的基本机制是什么？研究从TGF22到P19ARF的这一途径将加深我们对两种蛋白质在发育中的眼中运作方式的理解，并更好地定义可以导致玻璃体增生特征的人类疾病的遗传异常。但是，从更广泛的角度来看，这有可能阐明如何在癌细胞中控制ARF以及在发育过程中如何执行其他功能。 公共卫生相关性：ARF基因在预防原发性玻璃体增生和透明血管回归方面起着至关重要的作用，这对于正常视力至关重要。我们以前已经在发育中的眼睛中定义了其时间和空间限制的表达，但是这种表达模式的基础机制是完全未知的。我在该提案中的初步研究提供了第一个见解：TGF22在此过程中起着关键作用。该提案中的实验定义将定义TGF22实现这一目标的细胞和分子机制。