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

描述(由申请人提供)：人体血管系统、肺和肾脏的功能严重依赖于上皮细胞和内皮细胞形成正确的直径和长度的管子。然而，控制长期管子大小的机制却鲜为人知。这种认识的缺乏反映在对许多人类疾病缺乏有效的治疗上，其中管子大小控制有缺陷，如多囊肾病和血管畸形，以及我们无法控制管子大小来治疗非直接由管子大小缺陷引起的疾病。例如，增加血管管径的药物可能用于治疗缺血，而阻止血管管径增加的药物可能被用作抗血管生成药物，以阻止实体肿瘤的生长。果蝇气管系统是上皮管的分支网络，起着肺/血管系统的联合作用，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极好的系统。初步工作表明，NAK ATPase 13亚基NRV2是控制气管大小和组装间隔连接(相当于脊椎动物紧密连接的果蝇)所必需的。人类NAK-ATPase在多囊肾病(PKD)中定位错误，每800人中就有1人受到影响，其特征是管子异常增大。目前尚不清楚NAK ATPase错误定位是否是PKD的部分原因或结果，但初步研究表明，NAK ATPase先前未知的细胞连接功能可能在控制肾脏和其他肾小管器官的管径方面发挥关键作用。这项建议的第一个具体目标将是通过确定它们的几个组件是否以细胞自主方式起作用，以及几个间隔连接组件的已知细胞极性函数是否介导气管管径控制，来研究间隔连接复合体在管径控制中的作用。第二个目标是对NRV2-NAK-ATPase和两个果蝇Claudin在气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个基因，该基因似乎定义了与目前分析的基因不同的一类管径控制基因。

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.