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重要的远距离细胞信号传导机制。我们用一个模型系统来解决这些重要问题，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。我们的研究表明，在果蝇中，hedgehog （hh）基因在建立和调节胚胎中的片段以及翅盘的隔室边界和信号中心方面起着核心作用。我们最近的工作集中在其受体补丁（Ptc）和介导Hh信号转导的转录因子Cubitus interruptus （Ci）的活性上。Ptc和Ci的人类同源基因与包括癌症在内的许多人类疾病有关。具体的目标是在这个应用程序中提出：(1)完成前向遗传筛选，以确定Hh信号转导途径的额外成分；(2)利用互补分子方法确定Hh信号转导的新靶点；(3)表征Patched受体的结构和调控；(4)分析Ci向其抑制因子和激活因子形式的转化；(5)描述Hh从其合成位点移动到邻近或远处细胞中的受体的机制。

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.