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）：虽然Arf被广泛认为是一种肿瘤抑制基因，但它对小鼠眼睛发育也是必不可少的。缺乏Arf的小鼠天生失明，患有严重的发育性眼病，类似于称为持久性增生性原发性玻璃体炎的人类眼病。目前对控制Arf转录或其基因产物p19 Arf表达的基本机制知之甚少。我的总体目标之一是阐明驱动这一重要基因表达的基本机制。现有的教条认为，Arf作为一个“癌基因传感器”，这样它的表达被诱导在细胞携带异常或过度增殖信号从癌基因激活。单个细胞能够区分致癌刺激和同等强度的正常增殖信号（如发育期间发生的信号）的机制尚不清楚。然而，最近，我和我的实验室成员有了一个令人惊讶的发现，挑战了当前的范式。具体而言，在探索机制，p19 Arf防止原发性玻璃体增生的发展中的小鼠，我们发现，其启动子在一个精致的控制模式在小鼠发育过程中被激活。这一发现使我能够安全地得出结论，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，Tgf 22-/-表型的一部分类似于在Arf的情况下，我已经建立了转化生长因子2-2（Tgf 22）作为一个必不可少的调节p19 Arf和后者是所需的Tgf 22在体内和体外的抗有丝分裂作用。在这个提议中，我将利用现有的小鼠和细胞培养模型来弥补我知识中的三个关键空白：Tgf 2是否直接控制眼睛发育过程中p19 Arf的表达？Tgf 22发出的细胞内信号是什么？Arf启动子的基本作用机制是什么？研究从Tgf 22到p19 Arf的这一通路将加深我们对这两种蛋白质在发育中的眼睛中如何运作的理解，并更好地定义可能导致以玻璃体增生为特征的人类疾病的遗传异常。然而，从更广泛的角度来看，这可能为癌细胞中Arf的控制以及Tgf 2如何在发育过程中发挥其他功能提供了新的线索。 公共卫生相关性：Arf基因在预防原发性玻璃体增生和玻璃体血管退化中起着至关重要的作用，这些过程对正常视力至关重要。我们以前已经定义了它的时间和空间限制的表达在发展中的眼睛，但这种表达模式的机制是完全未知的。我在这个提议中的初步研究提供了第一个见解：Tgf 22在这个过程中起着关键作用。本提案中的实验将定义Tgf 22实现这一点的细胞和分子机制。