Establishment of Epithelial Planar Cell Polarity

上皮平面细胞极性的建立

• 批准号: 7151969
• 负责人: Marek Mlodzik
• 金额: $ 37.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151969
• 关键词: Address; Adult; Apical; Architecture; Binding; Biochemical; Biological Assay; Cell Polarity; Cell Shape; Cells; Cilia; Cultured Cells; Cytoskeletal Modeling; Data; Development; Disease; Drosophila genus; Epidermis; Epithelial; Epithelial Cells; Epithelium; Event; Evolution; Family; Felis catus; Genes; Genome; Goals; Growth Factor; Hair; Hybrids; Insecta; Invertebrates; Labyrinth; Ligands; Link; Malignant Neoplasms; Mammalian Oviducts; Mammals; Mediating; Medical; Membrane; Molecular; Molecular Genetics; Mutation; Organ; Organogenesis; Pathway interactions; Pattern; Process; Proteins; Proto-Oncogenes; RNA Interference; Range; Recruitment Activity; Regulation; Regulator Genes; Role; Sensory; Signal Transduction; Skin; Specificity; Structure; Tissues; Tumor Suppressor Proteins; Vertebrates; Yeasts; base; carcinogenesis; cell motility; cell type; deafness; extracellular; in vitro Assay; in vivo; interest; polarized cell; protein function; receptor; research study; response

DESCRIPTION (provided by applicant): Epithelial cells require correct polarity for their function. Their polarity and patterning is established during organogenesis. Epithelial cells are often polarized in two axes, in the apical-basolateral axis and in the plane of the epithelium, called planar cell polarization or PCP. Typical PCP examples include features of mammalian skin or internal organs, e.g. the inner ear epithelium with its sensory cilia, and insect cuticular structures in invertebrates. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination and the coordination of polarized cell shape changes in general. PCP is coordinated by long range signals, resulting in the activation of the Frizzled (Fz) receptor- and its associated signaling cascade (Fz/PCP signaling). The Fz/PCP pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization, including directed cell migration during mammalian gastrulation. Strikingly, Fz/PCP signaling is distinct from the canonical Wnt/Fz-B-Catenin pathway. The regulation of signaling specificity between these two pathways activated by the same receptors is only poorly understood, but critical for development and disease. Moreover, the link between Fz/PCP signaling and the resulting cellular responses, including cytoskeletal reorganization and specific transcriptional events are not yet understood. The scope of this application is to investigate the specific roles of newly identified genes required for PCP determination and cell shape change coordination. Their function in Fz/PCP signaling and/or in cellular polarization events will be investigated genetically and biochemically. A combination of in vivo studies in Drosophila, cell culture analyses and biochemical experiments will be utilized to achieve these goals. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities (including deafness in the case of the inner ear epithelium) and cancer (several components of the pathway are proto-oncogenes or tumor suppressors). Thus the information acquired in this application will both advance our understanding of cellular polarization and patterning, and will be of medical relevance, particularly for the study of carcinogenesis.

描述(申请人提供)：上皮细胞需要正确的极性才能发挥作用。它们的极性和模式是在器官发生过程中建立的。上皮细胞通常在两个轴上极化，即在顶端-基底外侧轴和在上皮平面内，称为平面细胞极化或PCP。典型的PCP例子包括哺乳动物皮肤或内脏的特征，例如内耳上皮及其感觉纤毛，以及无脊椎动物的昆虫角质结构。果蝇PCP的建立为研究PCP的测定和极化细胞形状变化的协调性提供了一个范例。PCP被长距离信号协调，导致FrizzledFZ受体及其相关的信号级联(FZ/PCP信号)的激活。FZ/PCP途径在整个进化过程中是保守的，也调节着协调的其他几个方面 细胞极化，包括哺乳动物原肠发育过程中细胞的定向迁移。引人注目的是，FZ/PCP 信号转导通路不同于经典的Wnt/Fz-B-catenin通路。由相同受体激活的这两条信号通路之间的信号特异性调节还知之甚少，但对发育和疾病至关重要。此外，FZ/PCP信号和由此产生的细胞反应之间的联系尚不清楚，包括细胞骨架重组和特定的转录事件。这项应用的范围是调查新发现的基因在PCP测定和细胞形状变化协调中所需的特定作用。它们在FZ/PCP信号和/或细胞极化事件中的功能将从遗传学和生物化学的角度进行研究。将结合果蝇体内研究、细胞培养分析和生化实验来实现这些目标。PCP的建立和Wnt/FZ信号转导过程与几种医学异常(包括内耳上皮的耳聋)和癌症(该通路的几个组成部分是原癌基因或肿瘤抑制基因)有关。因此，在这一应用中获得的信息将促进我们对细胞极化和模式的理解，并将具有医学意义，特别是对癌症发生的研究。