Factors Controlling Lens Epithelial Differentiation

控制晶状体上皮分化的因素

基本信息

批准号：
7633131
负责人：
DAVID CY BEEBE
金额：
$ 54.45万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-12-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633131
关键词：
Activins Affect Agonist Animals Attention Bone Morphogenetic Proteins Cataract Cataract Extraction Cell Cycle Proteins Cell Differentiation process Cell Proliferation Cells Chickens Development Embryo Epithelial Epithelial Cell Proliferation Epithelial Cells Excision Failure Fibroblast Growth Factor Fibroblast Growth Factor Receptors Fibrosis Gene Targeting Genes Genetic Genetic Models Grant Growth Growth Factor In Vitro Individual Knock-out Laboratories Lead Lens Fiber Life Light Mediating Mediator of activation protein Methods Microarray Analysis Mining Modification Molecular Mus Myofibroblast Nuclear Receptors PPAR gamma Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Phenotype Play Process Protein Family Publications Publishing Relative (related person)Research Research Personnel Retinoblastoma Protein Role Signal Pathway Signal Transduction System Tars Testing Transforming Growth Factor beta Transforming Growth Factors Vent Work body system bone morphogenetic protein receptors congenital cataract fiber cell in vivo inhibitor/antagonist insight interest knockout animal knockout gene lens lens induction member molecular phenotype programs receptor small molecule troglitazone

项目摘要

DESCRIPTION: Fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) play key roles in the development of the mammalian lens. However, the functions of individual BMP and FGF receptors and the mechanisms by which they regulate lens development are not known. Using conditional gene targeting, we show that FGF signaling provides important survival signals for lens epithelial and fiber cells and that different FGF receptors cooperate to promote fiber cell differentiation. BMP receptor-la (Alk3) is also required in fiber cell differentiation. A second type-1 BMP receptor, Alk2, regulates the rate of proliferation of lens epithelial cells. Deletion of Alk2 and Alk3 or Alk3 and a third BMP receptor, Alk6, causes failure of lens induction. None of these phenotypes occur when the BMP mediator Smad4 is deleted, suggesting that Smad-independent signaling is common in lens development. We propose to determine the mechanisms responsible for these phenotypes using immunochemical methods, microarray analysis, and by deleting other genes in the pathways activated by these receptors. Our studies also reveal that the retinoblastoma protein (pRb), a ubiquitous cell cycle regulatory protein, is unexpectedly hyperphosphorylated in terminally differentiated lens fiber cells. Using genetic models with defective fiber cell differentiation, we will determine how covalent modifications of pRb correlate with lens fiber cell differentiation. Exposure of lens cells to TGFbeta leads to pathological fibrosis, as often occurs following cataract surgery. Conditional deletion of TGFbetaRII shows that TGFbeta signaling is not the only cause of lens fibrosis. We will use gene targeting to test the interactions of TGFbeta with other factors in lens fibrosis. We also found that the PPARgamma agonist, troglitazone, blocks lens epithelial fibrosis. We will determine how PPARgamma signaling blocks fibrosis, including the possibility it interacts with the TGFbeta signaling system. The results of these studies are expected to provide important insight into the mechanisms of congenital cataracts and the fibrosis that commonly follows cataract surgery.

描述：成纤维细胞生长因子（FGFS）和骨形态发生蛋白（BMP）在哺乳动物镜头的发展中起关键作用。但是，尚不清楚单个BMP和FGF受体的功能以及它们调节晶状体发育的机制。使用条件基因靶向，我们表明FGF信号传导为晶状体上皮和纤维细胞提供了重要的生存信号，并且不同的FGF受体配合以促进纤维细胞分化。纤维细胞分化也需要BMP受体LA（ALK3）。第二型BMP受体ALK2调节晶状体上皮细胞的增殖速率。 ALK2和ALK3或ALK3的缺失以及第三个BMP受体ALK6导致镜头诱导的失败。当BMP介体SMAD4被删除时，这些表型都没有发生，这表明与SMAD独立的信号传导在晶状体发育中很常见。我们建议使用免疫化学方法，微阵列分析以及删除这些受体激活的途径中的其他基因来确定负责这些表型的机制。我们的研究还表明，无处不在的细胞周期调节蛋白视网膜母细胞瘤蛋白（PRB）在末端分化的透镜纤维细胞中意外地磷酸化。使用具有缺陷纤维细胞分化的遗传模型，我们将确定PRB的共价修饰与透镜纤维细胞分化如何相关。晶状体细胞暴露于TGFBETA会导致病理纤维化，因为白内障手术经常发生。 TGFBETARII的有条件缺失表明TGFBETA信号传导并不是晶状体纤维化的唯一原因。我们将使用基因靶向测试TGFBETA与晶状体纤维化中其他因素的相互作用。我们还发现，ppargamma激动剂Troglitazone阻断了透镜上皮纤维化。我们将确定PPARGAMMA信号如何阻止纤维化，包括它与TGFBETA信号系统相互作用的可能性。这些研究的结果预计将对先天性白内障机制以及通常在白内障手术进行的纤维化提供重要的见解。