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The Drosophila expansion Gene Controls Tracheal Tube Diameter

果蝇扩张基因控制气管管直径

基本信息

批准号：
8433039
负责人：
Lan Jiang
金额：
$ 32.43万
依托单位：
OAKLAND UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433039
关键词：
Achievement Affect Antibodies Apical Caliber Cell Count Cell physiology Cells Cephalic Chitin Complement Factor B Cytoplasm Cytoskeleton Data Defect Development Disease Drosophila genus Endocytosis Epithelial Genes Genetic Growth Factor Human Immunoblotting Invertebrates Kidney Kidney Diseases Knowledge Laboratories Lead Life Lung Mediator of activation protein Membrane Mitogen-Activated Protein Kinases Mutation Organ Organism Organogenesis Pathway interactions Phosphorylation Polycystic Kidney Diseases Process Protein Family Proteins RNA Interference Regulation Research Role Signal Pathway Signal Transduction Smad Proteins Smad protein Surveys System Testing Tissues Trachea Transforming Growth Factors Tube Tubular formation Vascular System Vertebrates Zebrafish apical membrane effective therapy human disease in vivo knock-down mutant novel prevent public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Distinct tube size is critical for the function of human tubular organs such as the lung, vascular system, and kidney. Aberrant tube sizes that arise during development can lead to devastating human illnesses such as Meckel kidney disease and polycystic kidney disease. However, the fundamental mechanisms that regulate tube size are still not well understood, preventing us from developing effective treatments for diseases caused by tube-size defects. Drosophila trachea provides a premier genetic system to investigate the fundamental mechanisms that regulate tube size. Mechanisms of tube-size control discovered in Drosophila trachea can be subsequently investigated in vertebrates, thereby extending our understanding of tube-size regulation in tubular organs in general. Recently, through a targeted RNAi knock down survey, we identified Expansion (Exp), an evolutionarily conserved and novel Smad-like protein, as an essential regulator of tube size in Drosophila trachea. Smad proteins generally function as mediators of Transforming Growth Factor-B (TGF-B) signaling. TGF- B signaling is known to control cell numbers within zebrafish cranial vessels, thereby regulating vessel diameter (Roman et al., 2002). However, our preliminary data indicated that TGF-B signaling and cell numbers were not involved in tube-size defects in exp mutants. Instead, the apical secretion of luminal proteins was defective, and the tracheal apical membrane was larger in exp mutants. In addition, phosphorylated MAP kinase (dp-Erk) levels were increased in exp mutants. Moreover, reducing Erk expression in exp mutants suppressed the observed tube-diameter defects. Other groups have shown that Epithelial Growth Factor (EGF) signaling phosphorylates Erk in Drosophila (Ohshiro et al., 2002) and that over-active EGF signaling expands tracheal tube diameter (Jeon et al., 2009), similar to our observations with exp mutants. Therefore, we hypothesize that Exp reduces EGF signaling to control the dynamic cellular processes required for tube-size regulation. We will test this hypothesis through the achievement of two specific Aims: (1) Identify the cellular processes that are regulated by Exp; 2) Determine how Exp regulates EGF signaling to control tube-size. Through the proposed experiments, we expect to define a novel role for Smad family proteins in regulating signaling pathways and downstream dynamic cellular processes to control tube-size. We expect that the results from the proposed study will advance the understanding of how tubes acquire their distinct sizes in tubular organs in Drosophila, and many mechanisms will be shared with other organisms, including vertebrates. Ultimately, such knowledge has the potential to provide novel targets for developing treatments for human diseases caused by tube-size defects.

描述（由申请方提供）：不同的管路尺寸对于人体管状器官（如肺、血管系统和肾脏）的功能至关重要。在发育过程中出现的异常管尺寸可能导致毁灭性的人类疾病，如梅克尔肾病和多囊肾病。然而，调节管尺寸的基本机制仍然没有得到很好的理解，这阻碍了我们开发有效的治疗方法来治疗由管尺寸缺陷引起的疾病。果蝇气管提供了一个首要的遗传系统，以调查的基本机制，调节管的大小。在果蝇气管中发现的管尺寸控制机制可以随后在脊椎动物中进行研究，从而扩展了我们对管状器官中管尺寸调节的理解。最近，通过一项有针对性的RNAi敲除调查，我们发现Expansion（Exp）是一种进化上保守且新型的Smad样蛋白，是果蝇气管管大小的重要调节因子。Smad蛋白通常作为转化生长因子-B（TGF-β）信号传导的介体起作用。已知TGF- B信号传导控制斑马鱼颅血管内的细胞数量，从而调节血管直径（Roman等人，2002年）。然而，我们的初步数据表明，TGF-B信号和细胞数量不参与exp突变体中的管尺寸缺陷。相反，管腔蛋白的顶端分泌是有缺陷的，和气管顶端膜较大的exp突变体。此外，磷酸化MAP激酶（dp-Erk）水平增加的exp突变体。此外，减少Erk表达的exp突变体抑制所观察到的管直径缺陷。其他研究小组已经表明，上皮生长因子（EGF）信号传导使果蝇中的Erk磷酸化（Ohshiro等人，2002）以及过度活跃的EGF信号传导扩大气管导管直径（Jeon等，2009），类似于我们对exp突变体的观察。因此，我们假设Exp减少EGF信号传导以控制管大小调节所需的动态细胞过程。我们将通过实现两个特定的目标来测试这一假设：（1）确定由Exp调节的细胞过程; 2）确定Exp如何调节EGF信号以控制管大小。通过所提出的实验，我们希望定义一个新的作用，Smad家族蛋白在调节信号通路和下游动态细胞过程中控制管的大小。我们预计，拟议研究的结果将促进对果蝇管状器官中管道如何获得不同尺寸的理解，并且许多机制将与其他生物（包括脊椎动物）共享。最终，这些知识有可能为开发治疗由管尺寸缺陷引起的人类疾病的方法提供新的目标。