EGF receptor mediated signaling in Drosophila

果蝇中 EGF 受体介导的信号传导

• 批准号: 8038020
• 负责人: Gertrud M. Schupbach
• 金额: $ 31.82万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038020
• 关键词: Address; Adverse effects; Affect; Anterior; Antineoplastic Agents; Biological Models; Cell Communication; Cell Differentiation process; Cells; Complex; Cytoplasm; DNA Damage; DNA Repair; Defect; Development; Dorsal; Down-Regulation; Drosophila genus; Drosophila melanogaster; Drug Delivery Systems; Egg Shell; Embryo; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Female; Funding; Gene Targeting; Genes; Germ Cells; Goals; Homologous Gene; Human; Link; Malignant Neoplasms; Mediating; Meiosis; Modeling; Modification; Molecular; Mutate; Mutation; Nature; Nuclear; Oocytes; Oogenesis; Organism; Ovarian Follicle; Ovary; Pathway interactions; Pattern; Peptide Initiation Factors; Phosphotransferases; Play; Process; Production; Proteins; RNA; Receptor Activation; Receptor Gene; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Repression; Research; Research Project Grants; Retrotransposon; Role; Signal Pathway; Signal Transduction; Stem cells; Tissues; Translational Regulation; Translations; Work; computerized data processing; egg; fight against; insight; malignant breast neoplasm; notch protein; novel; receptor; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): This research project investigates the mechanisms that activate the Drosophila Epidermal Growth Factor receptor (Egfr) during oogenesis, and the cellular pathways that mediate the response to this receptor tyrosine kinase in the ovarian follicle cells. Cell-cell communication plays an important role in the development of many tissues. Our model system focuses on signaling between the female germline and its surrounding follicle cells in the ovary of Drosophila melanogaster. We have shown that the Drosophila Egfr is expressed in the follicle cells and receives a highly controlled signal from the germline encoded by the gene gurken (grk). Restricted activation of the Egfr by Grk initiates several different follicle cell responses and is required for axis formation of the egg and embryo. We have also shown that grk expression in oogenesis can be regulated by a checkpoint mechanism. Problems in DNA repair during meiosis as well as other nuclear defects caused by retrotransposons, activate a meiotic checkpoint that controls translation of Grk in the oocyte cytoplasm. Our goal is to study the regulation of Gurken production in the germline and to analyze the patterning and differentiation processes that are activated in the follicle cells in response to receptor activation. Our specific aims are: 1) Checkpoint mediated control of Gurken production: 1A) The role of cutoff (cuff) in the piRNAi pathway. We have found that the gene cuff is a component of the piRNAi pathway that guards the germline against retrotransposon damage. Mutations in cuff activate a germline checkpoint. We will determine the molecular role of cuff in the piRNAi pathway and its effect on checkpoint activation. 1B) Translational regulation of gurken RNA. We will determine how the meiotic checkpoint regulates translation of grk. This will involve analysis of the gene vasa, as well as the translation initiation factor eIF1A that affects Grk protein levels in the checkpoint activated germline. 3) Analysis of the response pathway acting in the follicle cells of the ovary. We have defined several specific patterning responses to Egfr activation in the follicle cells. In particular, we have isolated mutations that affect posterior follicle cell differentiation and uncover interactions of Egfr signaling with the Notch pathway. We will analyze mutations in two genes that will allow us to describe the complex interactions of the two pathways in the posterior follicle cells. We will also compare the response of posterior follicle cells to that of dorsal follicle cells. Mutations in checkpoint genes, as well as unregulated activation of the human homologs of Egfr have been implicated in several forms of cancer. Our work will elucidate new roles of checkpoint genes, as well as analyzing the normal cellular pathways that regulate the activity of this receptor. It will also define downstream effector pathways operating in the follicle cell epithelium, a model system for epithelial development and differentiation. PUBLIC HEALTH RELEVANCE: This project investigates the regulation and the effects of the Drosophila Epidermal Growth Factor receptor. In humans, this type of receptor is frequently mutated in cancer, in particular in breast cancer, and novel drugs that target this receptor have already shown great promise in the fight against cancer. Our work identifies further genes that act in the same pathway as the receptor and these genes will provide new targets for specific cancer drugs as well as allowing us to address side effects of available cancer drugs.

描述（由申请人提供）：本研究项目研究卵子发生过程中激活果蝇表皮生长因子受体（Egfr）的机制，以及介导卵泡细胞中对该受体酪氨酸激酶反应的细胞途径。细胞间通讯在许多组织的发育中起着重要作用。我们的模型系统集中在雌性生殖细胞和其周围的卵泡细胞之间的信号在果蝇卵巢。我们已经证明，果蝇Egfr在卵泡细胞中表达，并从gurken（grk）基因编码的种系接收高度受控的信号。Grk对Egfr的限制性激活启动了几种不同的卵泡细胞反应，并且是卵子和胚胎轴形成所需的。我们还发现卵子发生中grk的表达可以通过检查点机制来调节。减数分裂过程中DNA修复的问题以及逆转录转座子引起的其他核缺陷激活了控制卵母细胞细胞质中Grk翻译的减数分裂检查点。我们的目标是研究生殖细胞中Gurken产生的调节，并分析在卵泡细胞中响应受体激活而激活的图案化和分化过程。我们的具体目标是：1）检查点介导的Gurken产生的控制：1A）截止（cuff）在piRNAi途径中的作用。我们已经发现，基因袖是保护生殖系免受逆转录转座子损伤的piRNAi途径的组分。袖口突变激活生殖细胞检查点。我们将确定cuff在piRNAi途径中的分子作用及其对检查点激活的影响。1B）Gurken RNA的翻译调节。我们将确定减数分裂检查点如何调节grk的翻译。这将涉及分析基因vasa，以及翻译起始因子eIF1A，其影响检查点激活的种系中的Grk蛋白水平。3)作用于卵巢卵泡细胞的反应通路分析。我们已经定义了几个特定的模式化反应，在卵泡细胞中的Egfr激活。特别是，我们已经分离出影响后卵泡细胞分化的突变，并揭示了Egfr信号与Notch通路的相互作用。我们将分析两个基因的突变，这将使我们能够描述后卵泡细胞中两个途径的复杂相互作用。我们还将比较后囊细胞和背囊细胞的反应。检查点基因的突变以及Egfr的人类同源物的不受调节的激活与几种形式的癌症有关。我们的工作将阐明检查点基因的新作用，并分析调节这种受体活性的正常细胞途径。它还将定义在滤泡细胞上皮中操作的下游效应子途径，这是上皮发育和分化的模型系统。 公共卫生相关性：该项目研究果蝇表皮生长因子受体的调节和作用。在人类中，这种类型的受体在癌症中经常发生突变，特别是在乳腺癌中，靶向这种受体的新型药物已经在对抗癌症方面显示出巨大的前景。我们的工作确定了与受体在同一途径中起作用的其他基因，这些基因将为特定的癌症药物提供新的靶点，并使我们能够解决现有癌症药物的副作用。