KANSAS INTERDISCIPLINARY CENTER FOR PKD RESEARCH

总体描述（直接取自应用程序）多囊肾病是整个动物王国观察。在人类中，它经常导致肾衰竭。人们普遍认为，这组疾病的破坏性后果在于肾小管段内囊肿的发展及其生长到巨大的尺寸。堪萨斯跨学科PKD研究中心将建立在基础和临床多囊肾疾病研究的丰富历史，在这个网站上，以解决有关囊肿发展和生长的分子和细胞发病机制的重要问题。该中心申请的主题是“多囊肾疾病中的多囊蛋白和信号转导”。四名已建立的PKD研究人员和一名新的研究人员是五个研究项目的首席研究员。一个行政核心将包括一个试点和可行性研究，由一个既定的分子生物学家谁是新的领域。所有这些项目都与多囊肾疾病的研究明确相关，范围从低等生物中多囊蛋白突变的研究到哺乳动物中囊肿发育和逐渐扩大的分子机制。低等动物是生物界高度保守功能的路线图。项目1将确定两个包囊形成基因CePKD-2和CeTg 737在C.优雅项目2将建立果蝇多囊肾病模型，以重建PKD 1/PKD 2介导的通路中的分子事件网络。项目3将测试PKD 1作为G蛋白偶联受体发挥作用的假设，当突变时会干扰早期胚胎发育以及肾脏和其他器官系统的发育。项目4将使用糖皮质激素诱导的肾脏谷胱甘肽S-转移酶Ya基因表达作为模型系统，检验多囊蛋白-1调节调节糖皮质激素受体活性的信号转导途径的假设。项目5将检验以下假设：在ADPKD中，细胞内cAMP水平升高会加速肾囊肿扩大，cAMP通过激活蛋白激酶A，刺激其他细胞机制，最明显的是ERK/MAP激酶途径。项目6将通过生产含有PKD 1中的初级突变和另一等位基因中的诱导性二次击中体细胞突变的小鼠来测试“二次击中”假说作为多囊肾病发病机制。这项研究的长期目标是为减缓或阻止多囊肾疾病的进展提供新的治疗方法。

OVERALL DESCRIPTION (Taken directly from the application) Polycystic kidney disease is observed throughout the animal kingdom. In humans it frequently leads to renal failure. It is widely believed that the destructive consequences of this group of diseases rest in the development of cysts within renal tubule segments and their growth to enormous size. The Kansas Interdisciplinary Center for PKD Research will build-on a rich history of basic and clinical polycystic kidney disease research at this site to address important questions about the molecular and cellular pathogenesis of cyst development and growth. The theme of this Center application is "Polycystin and signal transduction in polycystic kidney disease". Four established PKD investigators and one established researcher new to this field are Principal Investigators of five research projects. An administrative Core will include a pilot and feasibility study by an established molecular biologist who is new to the field. All of the projects are explicitly linked to the study of polycystic kidney disease and range from studies of polycystin mutations in lower organisms to the molecular mechanisms by which cysts develop and progressively enlarge in mammals. Lower animals serve as a road map to functions that are highly conserved in the biologic kingdom. Project 1 will determine the patterns of expression and comparative functions of two cyst-forming genes, CePKD-2 and CeTg737, in C. elegans. Project 2 will establish a model of polycystic kidney disease in Drosophila in order to reconstruct the network of molecular events in the PKD1/PKD2 mediated pathway. Project 3 will test the hypothesis that PKD1 functions as a G-protein coupled receptor that when mutated disturbs early embryological development and the development of the kidney and other organ systems. Project 4 will test the hypothesis that polycystin-1 regulates signal transduction pathways that modulate the activity of glucocorticoid receptor using the glucocorticoid-induced expression of the renal glutathione S-transferase Ya gene as a model system. Project 5 will test the hypothesis that in ADPKD, renal cyst enlargement is accelerated by elevated levels of intracellular cyclic AMP that, through the activation of protein kinase A, stimulates other cellular mechanisms, most notably the ERK/MAP kinase pathway. Project 6 will test the "second hit" hypothesis as a mechanism for the onset of polycystic kidney disease by producing mice containing both a primary mutation in PKD 1 and an inducible second-hit somatic mutation in the other allele. The long term goal is for this research to contribute to novel treatments to slow or arrest the progression of polycystic kidney disorders.