CELLULAR FUNCTION OF THE JUXTAGLOMERULAR APPARATUS

描述（改编自申请人的摘要）： 哺乳动物肾单位的器官（JGA）是连接肾单位的结构。 远端小管与肾小球血管极相连。 它位于肾单位 NaCl浓度随体内盐分变化很大的部位 平衡 申请人实验室的先前研究已经建立了 感测管状盐含量的变化，并且 传递到传入小动脉平滑肌细胞， 产生肾素的颗粒细胞。 这种信息流的结果是 调节肾小球血管张力和肾素分泌。 本申请结合了基因表达研究和功能研究。 研究，主要是在转基因动物，以澄清分子 这些反应的关键途径。 第一个具体目标是发展 并应用适合于研究GFR调节的方法， 在小鼠肾脏中，在单个肾单位和 器官水平，为以后的遗传学研究奠定基础。 改良动物 第二个目的是研究中断的影响， 血管紧张素和致密斑源性一氧化氮对 局部血管调节机制的设定点和敏感性，使用 ncNOS和AT1a受体无效突变的小鼠。 第三个目标是 评价腺苷和花生四烯酸之间的相互作用 在JGA的地方监管代谢。 第四个具体目标是 评估基因产物的作用，这些基因产物显示高水平的表达， JGA，但目前没有公认的监管作用。 的蛋白 对JGA功能的可能贡献是要检查催产素 受体、PTH相关蛋白和B6整合素。 这些研究的长期目标是了解细胞事件 负责局部控制肾素分泌和肾小球血管 对于控制体液至关重要的功能 容量和动脉血压。

DESCRIPTION (Adapted from the Applicant's Abstract): The juxtaglomerular apparatus (JGA) of the mammalian nephron is a structure which connects the distal tubule with the glomerular vascular pole. It is located at a nephron site where NaCI concentration varies considerably depending upon body salt balance. Previous studies in the applicant's laboratory have established that variations in tubular salt content are sensed, and signals are transmitted to the afferent arteriolar smooth muscle cells and renin-producing granular cells. The result of this information flow is regulation of glomerular vascular tone and renin secretion. The present application combines gene expression studies and functional studies, largely in transgenic animals, in order to clarify the molecular pathways critical for these responses. The first specific aim is to develop and apply methods that are suitable for studying regulation of GFR, blood flow and renin release in the mouse kidney at both the single nephron and organ level, in order to lay the foundation for later studies in genetically modified animals. The second aim is to study the effect of disruption in the regulation of angiotensin and of macula densa-derived nitric oxide on set point and sensitivity of the local vascular regulatory mechanisms, using mice with null mutations in ncNOS and AT1a receptors. The third aim is to evaluate the interactions between adenosine and arachidonic acid metabolities in local regulation in the JGA. The fourth specific aim is to evaluate the role of gene products which show high levels of expression in the JGA, but currently have no recognized regulatory role. Proteins whose possible contribution to JGA function is to be examined are the oxytocin receptor, PTH-related protein, and B6-integrin. The long term goal of these studies is to understand the cellular events responsible for local control of renin secretion and glomerular vascular tone, functions that are of central importance for the control of body fluid volume and arterial blood pressure.