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（例如肺，肾脏和血管系统）的功能主要取决于形成正确直径和长度的管的细胞。但是，控制管尺寸的机制知之甚少。这反映在缺乏对许多人类疾病的有效治疗中，其中管大小的控制有缺陷，例如多囊性肾脏疾病，以及我们无法控制管子大小来治疗由于管道大小缺陷而直接导致的疾病。例如，阻断血管管大小生长的药物可以用作抗血管生成药物来阻断实体瘤的生长。拟议的研究将定义多种机制的三个方面，这些机制使用果蝇气管作为模型系统来控制管子。果蝇气管是上皮管的细胞网络，可充当肺/血管系统的组合，并提供了一种强大的分子/遗传系统，用于研究使用体内方法和技术与脊椎动物模型困难或难以实现的管道控制的基本机制。我们的数据表明，保守的SRC激酶家族的成员控制果蝇气管发育和胚胎小鼠主动脉的发育过程中细胞生长的方向，果蝇formin ddaam与SRC42一起使用SRC42与东方气管生长一起使用。令人惊讶的是，SRC42和DDAAM形成了一种复合物，该复合物定义了一种与已知的顶端/基底极性和平面细胞极性途径不同的新极性途径。针对第一个目标提出的实验将确定SRC42和DDAAM是否要发送或接收具有对方向生长的信号，无论DDAAM是否充当SRC的调节剂或效应子，并识别SRC42和DDAAM方向功能的效应因素。在第二个目标中，我们将测试一个假设，即细胞体积增加调节气管细胞顶膜的程度，并确定哪些基因和途径介导了SRC42和DDAAM控制气管顶部表面积的能力。为了第三个目标，我们的初步数据表明，作用于保守的细胞生长和增殖途径的转录因子约克通过细胞死亡（凋亡）基因控制果蝇抑制剂（DIAP）的基因，尽管事实在气管系统中没有凋亡。在这个目标中，我们将检验约克的假设 也是控制气管管尺寸的五个已知途径中一个或多个的效应子 作为检验DIAP通过规范凋亡器蛋白的子集以调节管子尺寸的假设。总之，提出的实验的结果将提供对调节管子大小控制的分子机制的关键见解，这最终应导致治疗方法操纵管子的大小。