KANSAS INTERDISCIPLINARY CENTER FOR PKD RESEARCH

总体描述(直接取自申请)多囊肾病在整个动物界都能观察到。在人类中，它经常导致肾功能衰竭。人们普遍认为，这组疾病的破坏性后果在于肾小管段内的囊肿发展，并生长到巨大的尺寸。堪萨斯PKD跨学科研究中心将在这个地点建立在基础和临床多囊肾病研究的丰富历史基础上，以解决有关囊性发育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“多囊蛋白与多囊肾病的信号转导”。四名资深PKD调查员和一名新进入该领域的资深研究员是五个研究项目的首席调查员。行政核心将包括由一位新进入该领域的知名分子生物学家进行的试点和可行性研究。所有这些项目都明确地与多囊肾病的研究相关联，范围从低等生物的多囊蛋白突变研究到哺乳动物的包囊发育和逐渐扩大的分子机制。低等动物是生物界高度保守的功能的路线图。项目1将确定两个包囊形成基因CePKD-2和CeTg737在线虫中的表达模式和比较功能。项目2将建立果蝇多囊肾病模型，以重建PKD1/PKD2介导的途径中的分子事件网络。项目3将测试PKD1作为G蛋白偶联受体发挥作用的假设，当突变时，它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将以糖皮质激素诱导的肾脏谷胱甘肽S转移酶Ya基因表达为模型系统，验证多囊蛋白-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将检验这一假说，即在ADPKD中，细胞内cAMP水平的升高加速了肾囊肿的扩大，细胞内cAMP通过激活蛋白激酶A刺激其他细胞机制，最著名的是ERK/MAP激酶途径。项目6将通过培育同时含有PKD 1的初级突变和另一个等位基因的可诱导的二次突变的小鼠，来测试作为多囊肾病发病机制的“二次击中”假说。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.