Calcineurin in Congenital Urinary Tract Obstruction

先天性尿路梗阻中的钙调神经磷酸酶

• 批准号: 7380063
• 负责人: FENG CHEN
• 金额: $ 30.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380063
• 关键词: Alleles; BMP4; Behavior; Calcineurin; Calcineurin Pathway; Cell Line; Cells; Childhood; Complement; Development; Diagnostic Procedure; Epithelial; Epithelium; Etiology; Event; Genomics; Genotype; Human; Kidney Diseases; Kidney Failure; Knowledge; Lesion; Mesenchymal; Mesenchyme; Metanephric Diverticulum; Methods; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Obstruction; Pathogenesis; Pathway interactions; Proteomics; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Testing; Therapeutic; Tissues; Transducers; Transgenes; Ureteropelvic junction obstruction; Urinary tract; extracellular; immortalized cell; in vivo; insight; knowledge base; mutant; novel diagnostics; programs; response; tool; urinary; urinary tract obstruction

DESCRIPTION (provided by applicant): Congenital obstructive nephropathy is the principal cause of pediatric renal failure. The molecular and cellular lesions leading to congenital obstruction, however, are still largely undetermined. We have shown that the absence of calcineurin in the developing urinary tract mesenchyme, in the Pax3Cre Cnb1 mutants we generated, led to congenital obstructive nephropathy resembling Ureteropelvic Junction (UPJ) obstruction in humans. Our study has demonstrated a clear requirement for calcineurin in urinary tract development and provided us with materials and knowledge to further investigate the indispensable signaling events involved and the etiology of congenital obstructive nephropathy. We propose to first study the interactions between calcineurin and other signaling pathways known to be involved in urinary tract development. This will test the hypothesis that calcineurin is an indispensable signaling transducer for urinary tract development. This will also effectively connect our observations to the existing knowledge in this field and will provide a more comprehensive explanation, at the molecular and cellular level, for the pathogenesis of the congenital obstructive nephropathy. Then, we will develop primary and immortalized cell lines carrying the Cnb1 deletion to determine the effects of calcineurin inactivation in cellular behavior and signaling to test the hypothesis that calcineurin is required for interpreting various extracellular signals in cells of the urinary tract. We will also use genomic/proteomic approaches and molecular genetic methods to identify factors downstream of calcineurin in urinary tract development. Furthermore, we will complement the Pax3Cre-Cnb1 study with Cnb1 deletion in the ureteric bud (UB) derivatives to test the hypothesis that calcineurin has additional indispensable in vivo function in the UB and in the epithelial-mesenchymal interactions during urinary tract development. We will use these mutants to further analyze the interactions of the relevant signaling pathways in vivo. Results from the proposed studies will provide mechanistic insights into the function of calcineurin in normal and abnormal development of the urinary tract and the etiology of congenital obstructive nephropathy.

描述（由申请人提供）：先天性梗阻性肾病是小儿肾衰竭的主要原因。然而，导致先天性梗阻的分子和细胞病变在很大程度上仍未确定。我们已经证明，在我们产生的Pax 3Cre Cnb 1突变体中，发育中的尿路间充质中缺乏钙调神经磷酸酶，导致类似于人类肾盂输尿管连接部（UPJ）梗阻的先天性梗阻性肾病。我们的研究已经证明了尿路发育对钙调神经磷酸酶的明确需求，并为我们提供了材料和知识，以进一步研究所涉及的不可或缺的信号事件和先天性梗阻性肾病的病因。 我们建议首先研究钙调神经磷酸酶和其他已知参与尿路发育的信号通路之间的相互作用。这将测试的假设，钙调神经磷酸酶是一个不可缺少的信号转导的尿路发育。这也将有效地将我们的观察结果与该领域的现有知识联系起来，并在分子和细胞水平上为先天性梗阻性肾病的发病机制提供更全面的解释。然后，我们将开发携带Cnb 1缺失的原代和永生化细胞系，以确定钙调神经磷酸酶失活对细胞行为和信号传导的影响，以检验钙调神经磷酸酶是解释尿路细胞中各种细胞外信号所需的假设。我们还将使用基因组/蛋白质组学方法和分子遗传学方法来确定尿路发育中钙调神经磷酸酶下游的因素。此外，我们将补充Pax 3Cre-Cnb 1的研究与Cnb 1缺失的输尿管芽（UB）的衍生物，以测试的假设，钙调磷酸酶有额外的不可或缺的在体内功能的UB和上皮间质的相互作用在尿路发育。我们将利用这些突变体进一步分析体内相关信号通路的相互作用。从拟议的研究结果将提供钙调神经磷酸酶在正常和异常发育的尿路和先天性梗阻性肾病的病因机制的见解。