AREA: Mechanisms Underlying EGFR Signaling Distribution in Epithelial Tissues

领域：上皮组织中 EGFR 信号传导分布的机制

• 批准号: 8497018
• 负责人: Nir Yakoby
• 金额: $ 35.34万
• 依托单位: RUTGERS THE STATE UNIV OF NJ CAMDEN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497018
• 关键词: Accounting; Affect; Animals; Biological Assay; Biological Models; Biology; Bladder; Breast; Candidate Disease Gene; Cell Nucleus; Cell membrane; Cells; Colon; Communication; Computational Biology; Defect; Development; Disease; Dorsal; Drosophila genus; Drosophila melanogaster; Embryo; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Experimental Models; Future; Generations; Genetic; Genetic Models; Goals; Head and neck structure; In Situ Hybridization; Kidney; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Mathematics; Mediating; Membrane; Modeling; Modification; Molecular; Molecular Genetics; Molecular Models; Morphogenesis; Morphology; Nature; Nuclear; Oocytes; Oogenesis; Organ; Organism; Ovary; Pancreas; Pathology; Pathway interactions; Pattern; Perivitelline Space; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; Side; Signal Pathway; Signal Transduction; Signaling Molecule; Simulate; Structure; System; Testing; Tissues; Training; Transforming Growth Factor beta; Work; apical membrane; cancer type; computerized tools; drug development; graduate student; mathematical model; molecular modeling; neuronal cell body; protein distribution; public health relevance; research study; spatiotemporal; three dimensional structure; tool; undergraduate student

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a highly-conserved regulator of tissue development across animals. Faulty regulation of signaling is associated with developmental defects and pathologies such as cancers. The complexity of the EGFR activation network has been extensively studied; however, the coordinating mechanisms of multiple EGFR components are only partially understood. Furthermore, the mechanisms governing signaling changes that guide the formation of new morphologies across tissues have been only sparsely studied. The ovaries of Drosophila melanogaster provide a tractable genetic system to study mechanisms governing spatiotemporal differences of EGFR activation in the follicle cells (FCs), a 2D layer of epithelial cells surrounding the developing oocyte. Instructed mainly by the germline secreted TGF-beta-like ligand Gurken (GRK), the FCs form the 3D morphologies of the eggshell. One morphology is a structure with a lumen, the dorsal ridge, along the dorsal side of eggshells of numerous species from major clades of the genus Drosophila. Strikingly, we found quantitative and qualitative associations among EGFR activation domains, GRK protein distributions, and varieties of dorsal ridge morphologies. Combining molecular, genetic, and mathematical modeling approaches, we aim to determine the mechanisms governing different activation levels of EGFR in epithelial tissues across different species. Our experimental and modeling preliminary results support ligand localization to the oocyte and FCs' membranes, and the perivitelline space to underlie different signaling distributions in the 2D FCs. Considering the conserved nature of EGFR activation across animals, we expect to discover new mechanisms that control the levels of EGFR activation, which may become targets of drug development to treat tissue pathologies.

描述（由申请人提供）： 表皮生长因子受体（EGFR）信号通路是动物组织发育的高度保守调节因子。信号传导的基因调控与发育缺陷和病理如癌症相关。EGFR激活网络的复杂性已被广泛研究;然而，多个EGFR组分的协调机制仅被部分理解。此外，指导跨组织形成新形态的信号变化的机制只得到了很少的研究。果蝇的卵巢提供了一个易于处理的遗传系统，以研究卵泡细胞（FC）中EGFR激活的时空差异的机制， 卵母细胞周围的细胞。主要由生殖细胞分泌的TGF-β样配体Gurken（GRK）指导，FC形成蛋壳的3D形态。一种形态是具有内腔的结构，背脊，沿着果蝇属的主要分支的许多物种的蛋壳的背侧。引人注目的是，我们发现EGFR激活结构域，GRK蛋白分布和各种背嵴形态之间的定量和定性关联。结合分子，遗传和数学建模方法，我们的目标是确定不同物种上皮组织中EGFR不同激活水平的机制。我们的实验和建模的初步结果支持配体定位到卵母细胞和FC的膜，和卵周空间的基础不同的信号分布在二维FC。考虑到EGFR活化在动物中的保守性，我们期望发现控制EGFR活化水平的新机制，这可能成为治疗组织病理学的药物开发的靶点。