CELLULAR BIOLOGY OF CONGENITAL MURINE RENAL CYSTOGENESIS

尽管人类活动造成的发病率和死亡率很高， 多囊肾的病因有哪些？ 在这种疾病状态中逐渐扩大的情况在很大程度上是未知的。 的 应用程序的总体目标是确定 病理生理过程介导的形成和进行性 人常染色体显性遗传小鼠模型中肾小管囊肿的扩大 隐性多囊肾病，C57 BL/6 J cpk/cpk小鼠（CPK）。 在该模型的初步体内和体外研究的基础上， 已经产生了一个整体的实验假设， 两种特定蛋白质的异常表达和/或膜靶向， 表皮生长因子受体（EGF-R）和NaK腺苷 三磷酸酶（NaK ADAPOTH）-伴肾小管上皮增生，改变 经前庭运输，随后形成管状囊肿， 逐步扩大。 研究重点是四个具体目标， 批判性地评估实验假设： I.为了表征近端小管和收集管中EGF-R的表达， 肾小管上皮细胞在CPK囊肿形成的进行性阶段; 二.为了表征EGF-R激活在囊性上皮细胞中的作用， 利用EGF和TGF-α作为特异性配体的增生; 三.为了表征近曲小管细胞中NaK ATP酶的表达， CPK囊肿形成的进行性阶段;和 四.为了表征增加NaK ATP酶活性的机制， 或改变在囊性上皮中的位置可能导致溶质改变 运输 研究将在全肾、肾小管上皮细胞培养物和肾细胞培养物中进行。 上皮细胞来源于离散的控制或囊性肾单位节段. 管状囊肿的特定发育阶段和器官培养模型 调变 在这些模型中，具体的研究将集中在EGF-R和 NaK ATP酶亚基基因表达、蛋白质靶向和周转在 特异性质膜结构域，和蛋白质表达和活性， 正常和囊性进展阶段的明确上皮细胞 小管形成 拟议的研究将确定主要的致病过程， 在常染色体遗传性小鼠模型中启动和促进囊肿形成 隐性多囊肾 确定具体 在该动物模型中囊肿起始和囊肿促进过程可 肾囊肿的发病机制有哪些？ 常染色体隐性多囊肾病与其他人类疾病 states.

Despite the significant morbidity and mortality caused by human polycystic kidney diseases, the mechanisms by which cysts form and progressively enlarge in such disease states are largely unknown. The overall objective of the application is to identify the pathophysiological processes which mediate the formation and progressive enlargement of tubular cysts in a murine model of human autosomal recessive polycystic kidney disease, the C57BL/6J cpk/cpk mouse (CPK). On the basis of preliminary in vivo and in vitro studies in this model, an overall experimental hypothesis has been generated which links abnormal expression and/or membrane targeting of two specific proteins - the Epidermal Growth Factor Receptor (EGF-R) and the NaK Adenosine Triphosphatase (NaK ADPase)-with tubular epithelial hyperplasia, altered transtubular transport, and consequent tubular cyst formation and progressive enlargement. Studies focused on four specific aims will critically evaluate the experimental hypothesis: I. To characterize EGF-R expression in proximal tubule and collecting tubule epithelial cells at progressive stages of CPK cyst formation; II. To characterize the role of EGF-R activation in cystic epithelial hyperplasia utilizing EGF and TGF-alpha as specific ligands; III. To characterize NaK ATPase expression in proximal tubule cells at progressive stages of CPK cyst formation; and IV. To characterize the mechanisms by which increased NaK ATPase activity or altered location in cystic epithelia may lead to altered solute transport. Studies will be performed in whole kidneys, cell cultures of tubular epithelia derived from discrete control or cystic nephron segments at specific developmental stages, and organ culture models of tubular cyst modulation. In these models, specific studies will focus on EGF-R and NaK ATPase subunit gene expression, protein targeting and turnover in specific plasma membrane domains, and protein expression and activity in defined epithelia at progressive stages of normal and cystic tubulogenesis. The proposed studies will identify primary pathogenic processes which initiate and promote cyst formation in a murine model of autosomal recessive polycystic kidney disease. The identification of specific cyst-initiating and cyst-promoting processes in this animal model may provide insight into the pathogenesis of renal cyst formation in human Autosomal Recessive Polycystic Kidney Disease and other human disease states.