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

描述（由申请人提供）：人体血管系统、肺和肾的功能严重依赖于上皮细胞和内皮细胞形成正确直径和长度的管。然而，控制长期管尺寸的机制尚不清楚。这种认识的缺乏反映在对许多管大小控制有缺陷的人类疾病，如多囊肾病和血管畸形，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，增加血管管径的药物可以潜在地用于治疗缺血，而阻止血管管径增加的药物可以用作抗血管生成药物来阻止实体肿瘤的生长。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大小控制的基本机制提供了一个很好的系统。初步研究表明，NaK atp酶13亚基nrv2是气管管大小控制和分离连接（果蝇相当于脊椎动物的紧密连接）组装所必需的。人类NaK atp酶在多囊肾病（PKD）中定位错误，该病影响800人中有1人，其特征是异常的管增大。目前尚不清楚NaK atp酶错定位是PKD的部分原因还是结果，但初步研究表明，以前未发现的NaK atp酶的细胞连接功能可能在控制肾脏和其他管状器官的管大小中起关键作用。本提案的第一个具体目标将是通过确定分隔结复合物的几个成分是否在细胞自主作用以及几个分隔结成分的已知细胞极性功能是否介导气管管大小控制来研究分隔结复合物在管大小控制中的作用。第二个目标是对nrv2 NaK atp酶和两种果蝇（弯曲和巨气管）在气管管大小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种基因，这种基因似乎与目前分析的基因相比，定义了一种不同的管状控制基因。

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.