HEDGEHOG SIGNALING IN DEVELOPMENT AND DISEASE

发育和疾病中的刺猬信号传导

• 批准号: 7076500
• 负责人: THOMAS B. KORNBERG
• 金额: $ 28.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076500
• 关键词: Drosophilidae; arthropod genetics; biological signal transduction; gene expression profiling; gene induction /repression; genetic screening; paracrine; protein structure function; sonic hedgehog gene /protein; tissue /cell culture; transcription factor

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.

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很重要的长距离细胞信号传导机制。我们通过模型系统解决这些重要问题，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。我们的工作表明，在果蝇中，hedgehog (hh) 基因在建立和调节胚胎中的节段以及翼盘中的区室边界和信号中心方面发挥着核心作用。我们最近的工作重点是其受体 Patched (Ptc) 的活性和介导 Hh 信号转导的转录因子 Cubitus Interruptus (Ci)。 Ptc 和 Ci 的人类直系同源物与许多人类疾病有关，包括癌症。本申请提出的具体目标是：（1）完成正向遗传筛选，以确定 Hh 信号转导途径的其他成分； (2) 使用互补分子方法识别 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向阻遏物和激活物形式的转化； (5)描述Hh从其合成位点移动到邻近或远处细胞中与受体结合的机制。