The Role of FGF Receptors in Lens Development

 描述（由申请人提供）：异常FGF受体（FGFR）信号传导驱动许多人类癌症的恶性，也是许多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，在多种人类肿瘤中失活。FGFR是受体酪氨酸激酶（RTK），其通过激活AKT和ERK信号传导的信号转导途径激活许多细胞应答。尽管它们对人类健康至关重要，但对Fgfr刺激如何决定不同组织中不同细胞反应的详细机制理解仍然不完整。PTEN是一种磷酸酶，对脂质和蛋白质都表现出活性。最近的文献表明FGFR信号传导和PTEN信号传导在遗传上相互作用。眼透镜是一个相对简单的发育系统，其中FGFR信号传导起着重要作用。体内FGFR活性抑制导致透镜细胞凋亡和过度表达 或外源施用FGF导致透镜上皮细胞中的纤维细胞分化。到 为了剖析FGFR信号在透镜细胞存活和分化中的作用，本申请提出在体内和透镜外植体中遗传性地去除透镜中的FGFR信号，以将存活信号与分化信号分离。该提议将检验PTEN抑制FGFR介导的存活而不抑制FGFR介导的纤维细胞分化的假设。除了揭示PTEN调节FGFR信号传导的潜在机制之外，该提案的目的还将开发具有完整和缺陷的FGFR信号传导的透镜细胞在有和没有PTEN调节的分化条件下的第一个比较转录组。

 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.