The Role of FGF Receptors in Lens Development

 描述(申请人提供)：异常的成纤维细胞生长因子受体(FGFR)信号驱动了一些人类癌症的恶性，也是一些人类发育障碍的原因。同样，PTEN是一种众所周知的肿瘤抑制基因，在许多人类肿瘤中都是失活的。FGFRs是一种受体酪氨酸激酶(RTK)，通过激活AKT和ERK信号的信号转导途径激活许多细胞反应。尽管FGFR对人类健康至关重要，但对FGFR刺激如何在不同组织中决定不同的细胞反应的详细机制理解仍然不完整。PTEN是一种在脂质和蛋白质上都表现出活性的磷酸酶。最近的文献表明，FGFR信号和PTEN信号在遗传上相互作用。人工晶状体是一个相对简单的发育系统，FGFR信号在其中发挥着重要作用。体内抑制FGFR活性导致晶状体细胞凋亡和过度表达 外源性应用成纤维细胞生长因子可诱导晶状体上皮细胞向纤维细胞分化。至 剖析FGFR信号在晶状体细胞存活和分化中的作用，这一应用建议在体内和晶状体外植体中从基因上移除FGFR信号，以将存活信号和分化信号分离。该建议将检验PTEN在不抑制FGFR介导的纤维细胞分化的情况下抑制FGFR介导的存活的假说。除了揭示PTEN调控FGFR信号的潜在机制外，该方案的目的是在有和没有PTEN调控的分化条件下，建立第一个完整和缺失FGFR信号的晶状体细胞的比较转录组。

 DESCRIPTION (provided by applicant): Aberrant FGF receptor (FGFR) signaling drives the malignancy of a number of human cancers and also is responsible for a number of human developmental disorders. Likewise, PTEN is a well-known tumor suppressor gene that is inactivated in a large variety of human tumors. FGFRs are receptor tyrosine kinases (RTKs) that activate many cellular responses through a signal transduction pathway that activates both AKT and ERK signaling. Despite their central importance to human health, detailed mechanistic understanding of how Fgfr stimulation dictates diverse cellular responses in different tissues remains incomplete. PTEN is a phosphatase that exhibits activity both on lipids and proteins. Recent literature suggests that FGFR signaling and PTEN signaling genetically interact. The ocular lens is a relatively simple developmental system in which FGFR signaling plays an important role. Inhibition of FGFR activity in vivo leads to lens cell apoptosis and overexpression or exogenous administration of FGF leads to fiber cell differentiation in lens epithelial cells. To dissect the role of FGFR signaling in lens cell survival and differentiation, this application proposes to genetically remove FGFR signaling in the lens both in vivo and in lens explants to decouple survival signals from differentiation signals This proposal will test the hypothesis that PTEN inhibits FGFR- mediated survival without inhibiting FGFR-mediated fiber cell differentiation. In addition to revealing the underlying mechanism by which PTEN regulates FGFR signaling the aims of the proposal will develop the first comparative transcriptome of lens cells with intact and deficient FGFR signaling in differentiating conditions with and without regulation by PTEN.