Tube size control by Src and Yorkie/YAP

由 Src 和 Yorkie/YAP 控制管尺寸

基本信息

批准号：
8613770
负责人：
GREG J BEITEL
金额：
$ 28.83万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/8613770
关键词：
Actins Angiogenesis Inhibitors Aorta Apical Apoptosis Apoptosis Inhibitor Area Biological Models Blood Vessels Caliber Caspase Cell Death Cell Line Cell Polarity 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 Homologous Gene Human Image 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 polymerization public health relevance research study src-Family Kinases transcription factor transcriptome sequencing tumor growth ubiquitin-protein ligase

项目摘要

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）：肺、肾和血管系统等人体器官的功能很大程度上取决于形成正确直径和长度的管的细胞。然而，人们对控制管尺寸的机制知之甚少。这反映在许多人类疾病缺乏有效的治疗方法，其中许多人类疾病的管尺寸控制存在缺陷，例如多囊肾病，并且我们无法控制管尺寸来治疗并非直接由管尺寸缺陷引起的疾病。例如，阻止血管尺寸生长的药物可以用作抗血管生成药物来阻止实体瘤生长。拟议的研究将使用果蝇气管作为模型系统来定义控制管尺寸的多种机制的三个方面。果蝇气管是一个由上皮管组成的分枝网络，作为一个组合的肺/血管系统，并提供了强大的分子/遗传系统，用于使用脊椎动物模型难以或不可行的体内方法和技术研究管尺寸控制的基本机制。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 一起作用来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，定义了一种新的极性途径，该途径不同于已知的顶端/基底极性和平面细胞极性途径。第一个目标提出的实验将确定Src42和dDAAM是否发送或接收定向生长的信号，dDAAM是否充当Src的调节器或效应器，并确定Src42和dDAAM定向功能的效应器。在第二个目标中，我们将检验细胞体积的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，我们的初步数据表明，在保守的细胞生长和增殖途径中起作用的转录因子 Yorkie 通过名为果蝇凋亡抑制剂 (DIAP) 的细胞死亡（凋亡）基因控制管大小，尽管事实上气管系统无细胞凋亡。为此，我们将检验约克夏的假设也是控制气管导管尺寸的五种已知途径中的一种或多种的效应器测试 DIAP 通过典型凋亡感染蛋白的子集来调节管大小的假设。总之，所提出的实验结果将为调节管尺寸控制的分子机制提供重要的见解，这最终将导致能够治疗性地操纵管尺寸。