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: 6822559
• 负责人: GREG J BEITEL
• 金额: $ 27.12万
• 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/6822559
• 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，肺和肾脏的功能至关取决于形成正确直径和长度的管的上皮细胞和内皮细胞。但是，控制长期管子大小的机制知之甚少。缺乏理解反映在缺乏对许多人类疾病的有效治疗中，其中管大小的控制有缺陷，例如多囊肾脏疾病和血管畸形，以及我们无法控制管子大小而无法直接治疗疾病，而不是由于管尺寸的缺陷而直接。例如，增加血管管直径的药物可能可能用于治疗缺血，而阻断血管管尺寸增加的药物可以用作抗血管生成药物来阻断实体瘤的生长。果蝇气管系统是一种充当肺/血管组合系统的上皮管网络，为使用分子遗传方法研究管子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 13subunit NRV2是气管大小对照和组装分隔连接（果蝇等效的脊椎动物紧密连接）所需的。人NAK ATPase在多囊性肾脏疾病（PKD）中被错误地定位，该疾病会影响800人中的1人，其特征是管肿大。目前尚不清楚NAK ATPase错误定位是PKD的原因或结果的一部分，但是初步研究表明，NAK ATPase的先前未鉴定的细胞连接函数在控制肾脏和其他管状器官中的管子大小中起关键作用。该提案的第一个具体目的是通过确定其几个组件是否在细胞自治作用，以及几个隔离式连接组件的已知细胞极性功能是否介导气管大小的控制。第二个目的是对NRV2 NAK ATPase和两个果蝇Claudins的作用进行详细的分子和遗传研究，这些作用，即气管尺寸控制中的弯曲和巨张力。第三个目的是克隆并开始分析似乎定义了与当前分析的基因相比，它似乎定义了不同类型的管子对照基因的基因。