Tgf Beta 2 controls p19Arf During Eye Development

Tgf Beta 2 在眼睛发育过程中控制 p19Arf

• 批准号: 8696467
• 负责人: STEPHEN X SKAPEK
• 金额: $ 39.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696467
• 关键词: Accounting; Apoptosis; Applications Grants; Biochemical Genetics; Biochemical Pathway; Biology; Blood Vessels; Cell Culture Techniques; Cells; Child; Cues; DNA; Development; Disease; Elements; Endothelial Cells; Enhancers; Equilibrium; Evaluation; Eye; Eye Development; Eye diseases; Fostering; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomics; Goals; Government; Human; Hyperplasia; Knowledge; Laboratories; Left; Malignant Neoplasms; Microphthalmos; Modeling; Molecular; Molecular Biology; Mus; Nutrient; Oncogenes; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pericytes; Persons; Phase; Platelet-Derived Growth Factor Receptor; Play; Polymerase; Process; Proliferative Vitreoretinopathy; Proteins; Publishing; RNA Polymerase II; Regulatory Element; Reporting; Research; Research Infrastructure; Research Personnel; Retina; Retinal Detachment; Role; Signal Transduction; Signaling Protein; Staging; Therapeutic; Tissues; Trans-Activators; Transforming Growth Factor Beta 2; Transforming Growth Factors; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vascular System; Vision; Work; base; blind; cofactor; extracellular; fetal; in vivo; insight; lens; lens capsule; member; mouse model; ophthalmic artery; p19ARF; prevent; promoter; public health relevance; stem; tool; vessel regression

DESCRIPTION (provided by applicant): Although Arf is broadly known as a tumor suppressor gene, it also is essential for mouse eye development. Work from my laboratory has demonstrated that mice lacking Arf are born blind with a severe developmental eye disease, mimicking a human eye disease known as Persistent Hyperplastic Primary Vitreous (PHPV). This eye disease is due to failed involution of the hyaloid vasculature that provides nutrients to the developing eye. One of my overall goals is to elucidate the fundamental mechanisms by which the Arf gene product guides these critical vascular changes during normal eye development. Very little is known about basic mechanisms that control Arf transcription or the expression of its gene product, p19Arf. But, discoveries from my laboratory team over the last 21/2 years have provided new information challenging the existing dogma that Arf is primarily controlled by "abnormal" or "excessive" proliferation signals. Instead, we showed that an important signaling protein - Transforming Growth Factor b-2 (Tgfb2) - controls Arf expression during eye development. As importantly, Arf is absolutely essential for Tgfb2 to guide normal eye development. With these two findings, we established a new biochemical and genetic pathway that is essential for normal eye development and vision. Building naturally from our findings over the last 2 1/2 years, I intend to close three critical gaps in my understanding of how Tgfb2 can induce Arf expression: What are the DNA elements that flank the Arf gene to enhance its expression when stimulated by Tgfb2? How does Tgfb engage RNA polymerase II at the Arf promoter and how is this polymerase controlled once it is poised? How do the Tgfb dependent enhancers and trans-activating factors intersect with the transcriptional machinery to increase Arf expression? Studying this pathway from Tgfb2 to p19Arf will deepen our understanding of how the two proteins operate in the developing eye. It will also inform our knowledge of the broader role that Tgfb and p19Arf may play in perivascular cells that obviously have the capacity to either stabilize or destabilize underlying blood vessels. In the end, fully characterizing these molecular processes - including identifying the key regulatory elements in the gene and essential cofactors - will allow me to more effectively carry out genetics studies of patients with PHPV or similar eye diseases. From a broader perspective, though, the knowledge may also illustrate how Arf might be controlled in cancer and how Tgfbs may carry out other functions in development and disease.

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。我实验室的工作已经证明，缺乏Arf的小鼠天生失明，患有严重的发育性眼病，模仿人类的一种称为持久性增生性原发性玻璃体炎（PHPV）的眼病。这种眼病是由于为发育中的眼睛提供营养的玻璃体血管退化失败所致。我的总体目标之一是阐明Arf基因产物在正常眼睛发育过程中指导这些关键血管变化的基本机制。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。但是，在过去的21/2年里，我的实验室团队的发现提供了新的信息，挑战了现有的教条，即Arf主要是由“异常”或“过度”增殖信号控制的。相反，我们发现一个重要的信号蛋白-转化生长因子B-2（Tgfb 2）-控制Arf在眼睛发育过程中的表达。同样重要的是，Arf对于Tgfb 2指导正常的眼睛发育是绝对必要的。通过这两项发现，我们建立了一个新的生化和遗传途径，这对正常的眼睛发育和视力至关重要。基于我们过去两年半的研究结果，我打算填补我对Tgfb 2如何诱导Arf表达的理解中的三个关键空白：当Tgfb 2刺激时，Arf基因侧翼的DNA元件是什么？Tgfb如何在Arf启动子处接合RNA聚合酶II，以及一旦它处于平衡状态，该聚合酶如何被控制？Tgfb依赖性增强子和反式激活因子如何与转录机制交叉以增加Arf表达？研究从Tgfb 2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。它也将告知我们的知识，Tgfb和p19 Arf可能在血管周围细胞中发挥更广泛的作用，这些细胞显然有能力稳定或破坏下面的血管。最后，充分表征这些分子过程-包括确定基因中的关键调控元件和必要的辅助因子-将使我能够更有效地对PHPV或类似眼病患者进行遗传学研究。不过，从更广泛的角度来看，这些知识还可能说明Arf如何在癌症中受到控制，以及Tgfbs如何在发育和疾病中发挥其他功能。