RENAL TUBULOGENESIS AND THE ROLE OF HGF/SF AND SYNTAXINS

许多重要的器官，包括肾脏，都是由 间充质-上皮相互作用。这些互动的中介者是 肝细胞生长因子，又称散射因子(HGF-SF)。HGFISF是 间充质来源的生长因子及其配体在上皮细胞中的作用 Rnet受体。尽管HGFISF不是肾脏的唯一诱因 发育和小管发生，它在体内诱导小管发生 和体外II Madin-Darby犬肾(MDCK)细胞，这些细胞是 来源于犬肾小管上皮细胞。世代和 维持细胞的极性对上皮细胞的功能至关重要。至 建立和维持它们的极性，上皮细胞，包括MDCK，细胞 必须将质膜(PM)蛋白发送到TH(正确的顶端或 基准面PM初步结果表明，当HGF/SF诱导 小管生成发生MDCK细胞在分支时失去其极性 然后随着新的小管的形成，重新获得它们的极性。 近年来的一个重大发现是，几乎所有的细胞内 膜交通使用一种常见的膜融合机械。 合成素是膜融合的一个基因家族和组成部分 机械似乎指定正确的交付给不同的PM 表面。合成素2、3和4在上皮性器官中含量丰富。 肾脏。研究发现，Synaxins 2、3和4的表达存在差异 在MDCK细胞中，合成素3和4具有完全非 重叠分布。合成素是第一个参与的分子 膜融合机械，其异构体是不同的 局部化及其过度表达对极化的不同影响 膜流量。因此，他们是领先的候选人 至少包含维护所需的部分信息 细胞的极性。假设细胞极性的瞬间丧失是 肾小管形成的关键因素：合成素参与控制 细胞极化，从而导致小管形成。该表达式和 在HUF/SF诱导过程中，将检测合成素的定位 MDCK细胞的小管生成，啮齿动物肾脏的正常发育， 以及多囊肾等疾病状态下的异常发育 疾病和肾癌。为了直接检验这一假设， 表达不同的语法素的功能会受到干扰 过度表达、表达抑制和显性否定 变种人。如果合成素的表达对小管发生很重要， 可以考虑寻找改变语法表达的方法 在疾病状态下，也许是通过使用病毒载体的基因治疗。

Many vital organs, including the kidney, form as a result of a mesenchymal-epithelial interaction. A mediator of these interactions is hepatocyte growth factor, a. k. a. scatter factor, (HGF\SF). HGFISF is mesenchymally-derived growth factor and ligand for the epithelial c- rnet receptor. Though HGFISF is not the only inducer of renal development and tubulogenesis, it induces tubulogenesis both in vivo and in vitro ii Madin-Darby canine kidney (MDCK) cells, which are derived from canine renal tubular epithelium. Generation and maintenance of cell polarity is essential to epithelial cell function. To establish and maintain their polarity, epithelial, including MDCK, cells must send plasma membrane (PM) proteins to th( correct apical or basolateral PM. Preliminary results show that when HGF/SF induced tubulogenesis occurs MDCK cells lose their polarity as they branch out and then regain their polarity as the new tubules form. A major discovery in recent years is that almost all intracellular membrane traffic uses a common machinery for membrane fusion. Syntaxins are a gene family and component of the membrane fusion machinery that appear to specify correct delivery to the different PM surfaces. Syntaxins 2, 3, and 4 are abundant in epithelial organs, e.g. kidney. Syntaxins 2, 3, and 4 were found to be differentially expressed in MDCK cells, with syntaxins 3 and 4 having a completely non- overlapping distribution. Syntaxins are the first molecules that are part of the membrane fusion machinery, whose isoforms are differentially localized and whose overexpression has differential effects on polarized membrane traffic. Hence, they are the leading candidates for containing at least part of the information needed for the maintenance of cell polarity. The hypothesis is that transient loss of cell polarity i crucial for renal tubulogenesi: and syntaxins are involved in controlling cell poladty and therefore tubulogenesis. The expression and localization of syntaxins will be examined during HUF/SF induced tubulogenesis in MDCK cells, normal development of rodent kidneys, and abnormal development in disease states such a polycystic kidney disease and renal cell carcinoma. To directly test the hypothesis, the expression an function of different syntaxins will be perturbed by overexpression, inhibition of expression, and dominar negative mutants. If the expression of syntaxins is important for tubulogenesis, consideration can be given t finding ways to alter syntaxin expression in disease states, perhaps by gene therapy using viral vectors.