Tube size control by Src and Yorkie/YAP

由 Src 和 Yorkie/YAP 控制管尺寸

• 批准号: 9000711
• 负责人: GREG J BEITEL
• 金额: $ 28.78万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000711
• 关键词: Actins; Angiogenesis Inhibitors; Aorta; Apical; Apoptosis; Apoptosis Inhibitor; Area; Biological Models; Blood Vessels; Caliber; Caspase; Cell Death; Cell Line; Cell Proliferation; Cell Volumes; Cells; Communication; Complex; Data; Defect; Development; Disease; Dorsal; Drosophila genus; Embryo; Endothelial Cells; Epithelial; Epithelium; Genes; Genetic; Genetic Epistasis; Goals; Growth; Health; Homologous Gene; Human; Kidney; Lead; Length; Lung; Mediating; Modeling; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Morphogenesis; Mus; Names; Organ; Organ Size; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositol Phosphates; Polycystic Kidney Diseases; Process; Protein Tyrosine Kinase; Proteins; Regulation; Reporter; Research; Role; Signal Transduction; Solid Neoplasm; Surface; System; Techniques; Testing; Therapeutic; Trachea; Transcriptional Activation; Tube; Tubular formation; Ubiquitin; Vascular System; Work; apical membrane; cell growth; effective therapy; human disease; in vivo; insight; kidney vascular structure; member; mutant; novel; organ growth; planar cell polarity; polymerization; quantitative imaging; research study; src-Family Kinases; transcription factor; transcriptome sequencing; tumor growth; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The function of human organs such as the lung, kidney and vascular system are critically dependent on cells forming tubes of the correct diameter and length. However, the mechanisms controlling tube size are poorly understood. This is reflected in a lack of effective treatments for many human diseases in which tube-size control is defective, such as polycystic kidney disease, and our inability to control tube size to treat diseases that are not directly due to tube-size defects. For example, drugs that block vascular tube-size growth could be used as anti-angiogenic drugs to block solid tumor growth. The proposed research would define three aspects of the multiple mechanisms that control tube- size using the Drosophila tracheal as a model system. Drosophila trachea are a ramifying network of epithelial tubes that function as a combined pulmonary/vascular system and provides a powerful molecular/genetic system for investigating the basic mechanisms of tube-size control using in vivo approaches and techniques that are difficult or infeasible with vertebrate models. Our data show that members of the conserved Src kinase family control the orientation of cell growth during development of the Drosophila trachea and the embryonic mouse aorta, and that the Drosophila formin dDAAM works with Src42 to orient tracheal cell growth. Strikingly, Src42 and dDAAM form a complex that defines a new polarity pathway that is distinct from known apical/basal polarity and planar cell polarity pathways. The experiments proposed for the first aim would determine whether Src42 and dDAAM act to send or to receive signals that orient growth, whether dDAAM acts as a regulator or an effector of Src, and identify effectors of the Src42 and dDAAM orientation function. In the second aim, we will test the hypothesis that increases in cell volume regulate the extent of tracheal cell apical membrane and identify which genes and pathways mediate the ability of Src42 and dDAAM to control the tracheal apical surface area. For the third aim, our preliminary data show that the transcription factor Yorkie, which acts in conserved cell growth and proliferation pathways, controls tube size through the cell death (apoptosis) gene named Drosophila inhibitor of apoptosis (DIAP), despite the fact that there is no apoptosis in the tracheal system. In this aim, we will test that hypothesis that Yorkie is the effector of one or more of the five known pathways that controls tracheal tube size, as well as test the hypothesis that DIAP acts through a subset of canonical apoptosisfector proteins to regulate tube size. Together, the results of the proposed experiments will provide critical insights into the molecular mechanisms that regulate tube-size control, which should ultimately lead to the ability to therapeutically manipulate tube size.

描述（由申请人提供）：人体器官的功能，如肺、肾和血管系统，严重依赖于细胞形成正确直径和长度的管道。然而，控制管尺寸的机制尚不清楚。这反映在许多管大小控制有缺陷的人类疾病，如多囊肾病，缺乏有效的治疗方法，以及我们无法控制管大小来治疗不是直接由管大小缺陷引起的疾病。例如，阻止血管管大小生长的药物可以用作抗血管生成药物来阻止实体肿瘤的生长。提出的研究将定义三个方面的多种机制，控制管的大小使用果蝇气管作为模型系统。果蝇气管是上皮管的分支网络，作为肺/血管系统的组合，为研究管大小控制的基本机制提供了强大的分子/遗传系统，这些方法和技术在脊椎动物模型中很难或不可行的。我们的数据表明，保守的Src激酶家族成员在果蝇气管和胚胎小鼠主动脉发育过程中控制细胞生长的方向，并且果蝇formin dDAAM与Src42一起作用以定向气管细胞的生长。引人注目的是，Src42和dDAAM形成了一个复合物，定义了一个新的极性途径，不同于已知的顶/基极性和平面细胞极性途径。为第一个目标提出的实验将确定Src42和dDAAM是发送还是接收定向生长的信号，dDAAM是Src的调节剂还是效应器，并确定Src42和dDAAM定向功能的效应器。在第二个目标中，我们将验证细胞体积增加调节气管细胞顶膜范围的假设，并确定哪些基因和途径介导Src42和dDAAM控制气管顶表面积的能力。对于第三个目标，我们的初步数据显示，尽管气管系统中没有细胞凋亡，但在保守的细胞生长和增殖途径中起作用的转录因子Yorkie通过名为Drosophila inhibitor of apoptosis （DIAP）的细胞死亡（凋亡）基因来控制管的大小。为了达到这个目的，我们将检验Yorkie