Signaling Mechanisms of Lens Development

晶状体发育的信号机制

基本信息

批准号：
8424295
负责人：
Xin Zhang
金额：
$ 36.58万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424295
关键词：
Ablation Adaptor Signaling Protein Affect Anophthalmos Binding Biochemical Cell Culture Techniques Cell Proliferation Cells Congenital Abnormality Data Defect Development Diagnosis Disease Eye Abnormalities Failure Fibroblast Growth Factor Fibroblast Growth Factor Receptors Future Genes Genetic Genetic Predisposition to Disease Goals Grant Health Heparitin Sulfate Human Individual Knock-out Knowledge Lead Live Birth Malignant Neoplasms Mediating Metabolic syndrome Microphthalmos Modeling Molecular Movement Mutant Strains Mice Pathway interactions Patients Phenotype Phosphatidylinositols Phosphotransferases Protein Tyrosine Phosphatase Proteins Regulation Role Signal Pathway Signal Transduction Signaling Molecule Syndrome Testing Therapeutic Intervention Vision research Work base extracellular lens lens induction lens morphogenesis mutant prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Anophthalmia and extreme microphthalmia occur in 1 per 5000 live births, but nearly all of them have unknown genetic etiology. Defective lens development is a major cause of these congenital eye diseases, because the human lens is the culmination of elaborate cell proliferation, differentiation and movement, requiring precise regulation by signaling pathways. A molecular understanding of lens development could potentially lead to new ways of diagnosing and treating congenital eye diseases originated from defective lens genesis. We have identified Shp2, a protein tyrosine phosphatase, as a key factor in orchestrating lens morphogenesis by regulating FGF signaling. In this application, we will focus on the mechanism of Shp2 regulated FGF signaling in lens development. Using conditional mutant mice and cell culture models, we will identify the molecular interactions in mediating FGF signaling during lens induction and differentiation. Furthermore, we will test the hypothesis that Ras and/or PI3K signaling are necessary and sufficient for FGF signaling in lens development. As a major signaling pathway, perturbation in FGF signaling can cause not only congenital diseases, but also metabolic syndromes and cancer. Therefore, study of FGF signaling has far reaching implications for both human health and vision research.

描述（由申请人提供）：每5000个活产的恐怖分子和极端的微感染症发生，但几乎所有的活产病学都未知。有缺陷的晶状体发育是这些先天性眼部疾病的主要原因，因为人类晶状体是精心的细胞增殖，分化和运动的顶点，需要通过信号通路进行精确调节。对晶状体发育的分子理解可能会导致诊断和治疗先天性眼部疾病的新方法起源于有缺陷的晶状体起源。我们已经将SHP2（一种蛋白质酪氨酸磷酸酶）确定为通过调节FGF信号来策划晶状体形态发生的关键因素。在此应用中，我们将重点介绍晶状体开发中SHP2调节的FGF信号的机制。使用条件突变小鼠和细胞培养模型，我们将在镜头诱导和分化过程中介导FGF信号传导中的分子相互作用。此外，我们将检验以下假设：RAS和/或PI3K信号对于晶状体发育中的FGF信号传导是必需的，并且足够。作为主要信号通路，FGF信号的扰动不仅会导致先天性疾病，还会引起代谢综合征和癌症。因此，对FGF信号的研究对人类健康和视力研究都具有远大影响。