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: 9247201
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247201
• 关键词: Apoptosis; Biochemical Genetics; Biochemical Pathway; Biology; Blood Vessels; Cell Culture Techniques; Cells; Child; Cues; DNA; Development; Disease; Elements; Endothelial Cells; Enhancers; Equilibrium; Eye; Eye Development; Eye diseases; Fostering; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genetic study; Goals; Human; Hyperplasia; Knowledge; Laboratories; Malignant Neoplasms; Microphthalmos; Modeling; Molecular; Molecular Biology; Mus; Nutrient; Oncogenes; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pericytes; Phase; Platelet-Derived Growth Factor beta Receptor; Play; Polymerase; Process; Proliferative Vitreoretinopathy; Proteins; RNA Polymerase II; Regulatory Element; Reporting; Research; Research Infrastructure; Research Personnel; Retina; Retinal Detachment; Role; Signal Transduction; Signaling Protein; Therapeutic; Tissues; Traction; Trans-Activators; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vascular System; Vision; Work; base; blind; cofactor; extracellular; fetal; gene product; human genomics; 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 ß-2 (Tgfß2) - controls Arf expression during eye development. As importantly, Arf is absolutely essential for Tgfß2 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 Tgfß2 can induce Arf expression: What are the DNA elements that flank the Arf gene to enhance its expression when stimulated by Tgfß2? How does Tgfß engage RNA polymerase II at the Arf promoter and how is this polymerase controlled once it is poised? How do the Tgfß dependent enhancers and trans-activating factors intersect with the transcriptional machinery to increase Arf expression? Studying this pathway from Tgfß2 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 Tgfß 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 Tgfßs 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，但它对于小鼠眼睛的发育也是必需的。我实验室的工作表明，缺乏 Arf 的小鼠生来就会失明，患有严重的发育性眼病，类似于人类眼病，称为持续性增生性原发性玻璃体 (PHPV)。这种眼病是由于为发育中的眼睛提供营养的玻璃体脉管系统复旧失败所致。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引导这些关键血管变化的基本机制。人们对控制 Arf 转录或其基因产物 p19Arf 表达的基本机制知之甚少。但是，我的实验室团队在过去 21/2 年的发现提供了新的信息，挑战了现有的教条，即 Arf 主要由“异常”或“过度”增殖信号控制。相反，我们发现一种重要的信号蛋白 - 转化生长因子 ß-2 (Tgfß2) - 控制眼睛发育过程中的 Arf 表达。同样重要的是，Arf 对于 Tgfß2 指导正常眼睛发育绝对至关重要。通过这两项发现，我们建立了一条新的生化和遗传途径，这对于正常的眼睛发育和视力至关重要。根据我们过去 2 1/2 年的发现，我打算弥合我对 Tgfß2 如何诱导 Arf 表达的理解中的三个关键差距：当 Arf 基因受到 Tgfß2 刺激时，其侧翼有哪些 DNA 元件可增强其表达？ Tgfß 如何在 Arf 启动子处与 RNA 聚合酶 II 结合？这种聚合酶一旦准备就绪，如何受到控制？ Tgfß 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 Tgfß2 到 p19Arf 的这条通路将加深我们对这两种蛋白质如何在发育中的眼睛中发挥作用的理解。它还将使我们了解 Tgfß 和 p19Arf 在血管周围细胞中可能发挥的更广泛作用，这些细胞显然具有稳定或破坏底层血管的能力。最后，充分表征这些分子过程——包括识别基因中的关键调控元件和必需的辅助因子——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，这些知识还可以说明 Arf 如何在癌症中得到控制，以及 Tgfßs 如何在发育和疾病中发挥其他功能。