Physiologic role of collecting duct ciiliary proteins

描述（由申请方提供）：当前提案的目的是研究集合管初级纤毛在调节肾脏电解质和水排泄以及全身血压中的生理作用。最近的研究表明，在肾小管上皮细胞的中央纤毛在肾脏病理中起着重要的作用，许多肾囊肿的基因产物本地化，至少部分地，在初级纤毛，这些囊性成分的突变导致囊性肾病。相比之下，初级纤毛在正常生理条件下调节肾小管上皮细胞的作用是未知的。一个流行的假设是，初级纤毛，凭借其顶端的位置，传递机械信号，如小管流体流速，提供细胞的信息，细胞的方向。这一信息在保持小管细胞处于分化状态中可能是重要的。此外，这种机械转导可能有助于连接小管液体流速与跨上皮电解质和水的运输。这种系统在调节集合管钾分泌和钠和水的重吸收方面可能特别重要。如果是这样的话，那么集合管中的初级纤毛最终可能在控制全身血压方面至关重要。为了检验这一可能性，目前的建议将有两个主要的具体目标： 1)为了产生具有可能参与转导流量调节纤毛机械感觉的基因（pkdl或Tg 737）的时间控制的集合管特异性敲除的小鼠。由于传统的纤毛基因敲除导致囊肿形成，目前的研究将急性敲除目标纤毛基因在成人。目的是建立睫状体基因敲除的动物模型，以便在肾囊肿发生前进行生理学分析。 2)确定小鼠中纤毛蛋白表达（多囊蛋白-1或polaris）缺乏是否会导致全身血压改变和/或肾脏电解质和水排泄改变。集合管电解质和水输送将发生急性或慢性变化，并将确定肾脏适当补偿肾脏盐和水排泄的能力以及血压反应。 这些研究将开始检查肾脏生理学中一个非常重要但尚未探索的领域-集合管通过初级纤毛与其环境相互作用的能力，以调节肾脏盐和水的排泄以及全身血压。这些研究的目的是为随后的机制分析纤毛调节肾小管运输过程提供基础。最重要的是，这项工作可能揭示了控制血压和高血压发展的新机制。

DESCRIPTION (provided by applicant): The purpose of current proposal is to study the physiologic role of collecting duct primary cilia in regulating renal electrolyte and water excretion and systemic blood pressure. Recent studies indicate that central cilia in renal tubular epithelial cells play an important role in renal pathology; many renal cystic disease gene products localize, at least in part, to the primary cilia, and mutations in these cystic components leads to cystic kidney disease. In contrast, the role of primary cilia in regulating renal tubular epithelial cells under normal physiologic conditions is unknown. A prevailing hypothesis is that primary cilia, by virtue of their apical location, transduce mechanical signals such as tubule fluid flow rate, that provide the cell with information about cell orientation. This information may be important in keeping tubule cells in a differentiated state. In addition, such mechanotransduction may help link tubule fluid flow rate with transepithelial electrolyte and water transport. Such a system may be particularly important in regulating collecting duct secretion of potassium and reabsorption of sodium and water. If so, then primary cilia in collecting duct may ultimately be vitally important in the control of systemic blood pressure. To test this possibility, the current proposal will have two major specific aims: 1) To generate mice with temporally-controlled collecting duct-specific knockout of genes likely to be involved in transducing flow-regulated cilia mechanosensation (pkdl or Tg737). Since conventional ciliary gene knockouts lead to cyst formation, the current study will acutely knockout target ciliary genes in adults. The goal is to develop animal models of ciliary gene knockout the permit physiologic analysis prior to the development of renal cysts. 2) To determine if deficiency of ciliary protein expression (polycystin-1 or polaris) in mice leads to altered systemic blood pressure and/or altered renal electrolyte and water excretion. Collecting duct electrolyte and water delivery will be acutely or chronically changed and the ability of the kidney to appropriately compensate renal salt and water excretion, as well as the blood pressure response, will be ascertained. These studies will begin to examine a fundamentally important yet largely unexplored area in renal physiology - the ability of the collecting duct to interact with its environment, through the primary cilia, to regulate renal salt and water excretion and systemic blood pressure. Such studies are designed to provide the groundwork for subsequent mechanistic analysis of ciliary regulation of renal tubule transport processes. Most importantly, this work may shed light on novel mechanisms involved in control of blood pressure and development of hypertension.