Tube-size control by the Na K ATPase & septate junctions

通过 Na K ATP 酶控制试管尺寸

• 批准号: 6914969
• 负责人: GREG J BEITEL
• 金额: $ 27.91万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914969
• 关键词: Drosophilidae; RNA interference; cell growth regulation; cellular polarity; gene interaction; gene mutation; genetic recombination; intercellular connection; membrane proteins; molecular cloning; nerve /myelin protein; phenotype; protein structure function; respiratory epithelium; sodium potassium exchanging ATPase; trachea

DESCRIPTION (provided by applicant): The functions of the human vascular system, lung and kidney are critically dependent on epithelial and endothelial cells forming tubes of the correct diameters and lengths. However, the mechanisms controlling long-term tube size are poorly understood. This lack of understanding is reflected in the lack of effective treatments for many human diseases in which tube-size control is defective, such as polycystic kidney disease and vascular malformations, and our inability to control tube size to treat diseases not directly due to tube-size defects. For example, drugs that increase vascular tube diameter could potentially be used to treat ischemia, while drugs that block vascular tube size increases could be used as anti-angiogenic drugs to block solid tumor growth. The Drosophila tracheal system, a ramifying network of epithelial tubes that functions as a combined pulmonary/vascular system, provides an excellent system for using molecular genetic approaches to investigate the basic mechanisms of tube-size control. Preliminary work shows that the NaK ATPase 13subunit nrv2 is specifically required for tracheal tube-size control and for assembling septate junctions, the Drosophila equivalent of vertebrate tight junctions. The human NaK ATPase is mislocalized in polycystic kidney disease (PKD), which affects 1 in 800 people and is characterized by abnormal tube enlargement. It is unclear whether NaK ATPase mislocalization is part of the cause of, or the result of, PKD, but the preliminary studies suggest that a previously unidentified cell junctional function of the NaK ATPase could play a critical role in controlling tube size in the kidney and other tubular organs. The first specific aim of this proposal will be to investigate the role of septate junction complexes in tube-size control by determining whether several of their components act cell-autonomously and whether a known cell polarity function of several septate junction components mediates tracheal tube-size control. The second aim is to perform detailed molecular and genetic investigations of the roles of the nrv2 NaK ATPase and two Drosophila claudins, sinuous and megatrachea in tracheal tube-size control. The third aim is to clone and begin analyzing another gene that appears to define a distinct class of tube-size control gene than currently analyzed genes.

描述（由申请人提供）：人体血管系统、肺和肾的功能很大程度上取决于形成正确直径和长度的管的上皮细胞和内皮细胞。然而，人们对控制长期管尺寸的机制知之甚少。这种认识的缺乏反映在许多人类疾病缺乏有效的治疗方法，这些疾病的输卵管尺寸控制存在缺陷，例如多囊肾病和血管畸形，以及我们无法控制输卵管尺寸来治疗并非直接由输卵管引起的疾病。尺寸缺陷。例如，增加血管直径的药物可潜在地用于治疗缺血，而阻止血管尺寸增加的药物可用作抗血管生成药物以阻止实体瘤生长。果蝇气管系统是一个由上皮管组成的分支网络，具有肺/血管系统的功能，为利用分子遗传学方法研究管尺寸控制的基本机制提供了一个极好的系统。初步研究表明，NaK ATPase 13 亚基 nrv2 是气管尺寸控制和组装隔膜连接（果蝇相当于脊椎动物紧密连接）所必需的。人类 NaK ATP 酶在多囊肾病 (PKD) 中定位错误，该病影响每 800 人中就有 1 人，其特点是肾管异常增大。目前尚不清楚 NaK ATP 酶的错误定位是否是 PKD 的原因或结果，但初步研究表明，先前未识别的 NaK ATP 酶的细胞连接功能可能在控制肾脏和肾管大小方面发挥关键作用。其他管状器官。该提案的第一个具体目标是通过确定隔膜连接复合物的多个组件是否以细胞自主方式起作用以及多个隔膜连接组件的已知细胞极性功能是否介导气管导管尺寸来研究隔膜连接复合物在管尺寸控制中的作用控制。第二个目标是对 nrv2 NaK ATP 酶和两种果蝇claudins、蜿蜒气管和巨气管在气管管尺寸控制中的作用进行详细的分子和遗传学研究。第三个目标是克隆并开始分析另一个基因，该基因似乎定义了与当前分析的基因不同的管大小控制基因类别。