HEDGEHOG SIGNALING IN DEVELOPMENT AND DISEASE

描述（由申请人提供）：本研究的长期目标是了解对发育和疾病至关重要的长距离细胞信号传导机制。我们解决这些重要的问题与模型系统，应用其强大的遗传和分子技术来识别和分析关键基因和过程。我们的工作表明，在果蝇中，hedgehog（hh）基因在胚胎中的节段和翼盘中的隔室边界和信号中心的建立和调节中起着核心作用。我们最近的工作主要集中在其受体Patched（Ptc）和介导Hh信号转导的转录因子Cubitus interruptus（Ci）的活性上。Ptc和C1的人类直系同源物已经涉及许多人类疾病，包括癌症。在本申请中提出的具体目的是：（1）完成正向遗传筛选以鉴定Hh信号转导途径的额外组分;（2）使用互补分子方法鉴定Hh信号转导的新靶标;（3）表征Patched受体的结构和调节;（4）分析Ci向其阻遏物和激活物形式的转化;（5）描述了Hh从其合成位点移动到邻近或远处细胞中与其受体结合的机制。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the mechanisms of long-distance cell signaling that are important to development and to disease. We address these important issues with a model system, applying its powerful genetic and molecular techniques to identify and analyze key genes and processes. Our work has shown that in Drosophila, the hedgehog (hh) gene plays a central role setting up and regulating both the segments in the embryo and the compartment borders and signaling centers in the wing disc. Our recent work has focused on the activities of its receptor, Patched (Ptc) and on the transcription factor that mediates Hh signal transduction, Cubitus interruptus (Ci). The human orthologs of both Ptc and Ci have been implicated in a number of human diseases, including cancer. Specific aims are proposed in this application to: (1) complete a forward genetic screen to identify additional components of the Hh signal transduction pathway; (2) identify novel targets of Hh signal transduction using complementary molecular approaches; (3) characterize the structure and regulation of the Patched receptor; (4) analyze the conversion of Ci to its repressor and activator forms; and (5) describe the mechanism by which Hh moves from its sites of synthesis to engage its receptor in neighboring or a distant cells.