Regulation of calcium signaling by the PKD2 gene product

PKD2 基因产物对钙信号传导的调节

基本信息

批准号：
8107253
负责人：
Leonidas Tsiokas
金额：
$ 36.85万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107253
关键词：
Address Affect American Autosomal Dominant Polycystic Kidney Binding Biochemical Calcium Signaling Cell Culture Techniques Cell membrane Cells Complex Data Defect Development Ectopic Expression Embryo Epithelial cyst Extracellular Domain Family Genes Glycoproteins Hereditary Disease Heterozygote Ion Channel Kidney Knowledge Ligands Light Limb structure Link Liver Mediating Membrane Proteins Missense Mutation Modeling Molecular Mus Mutation Names PKD1 gene PKD2 gene Pancreas Pathway interactions Phenotype Phosphatidylinositol 4,5-Diphosphate Process Property Proteins Publishing Regulation Role Signal Pathway Signal Transduction Staging Stimulus Testing Wnt proteins Zebrafish base beta catenin body system chemical genetics effective therapy extracellular genetic manipulation in vivo kidney cell kidney epithelial cell member mutant protein function protein kinase D receptor reconstitution research study therapeutic development

项目摘要

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases. It affects 1 in 1000 Americans with the development of epithelial cysts in the kidney, liver, and pancreas. Naturally occurring mutations in two separate genes, PKD1 and PKD2, are responsible for the vast majority (~99%) of all cases of ADPKD. PKD1 encodes a large plasma membrane protein with a long extracellular domain, while PKD2 encodes an ion channel of the TRP superfamily (currently named, TRPP2). We and others have shown that PKD1 physically interacts with TRPP2 to form an ion channel complex (PKD1/TRPP2) that links extracellular stimuli to Ca2+ influx. However, it still remains unknown how mutations in these genes cause ADPKD. Defects in the limb of the Wnt pathway not associated with beta-catenin (non-canonical Wnt pathway) have been also associated with cystogenesis. We propose that there is a functional interaction between PKD1/TRPP2-mediated signaling and the non-canonical Wnt pathway. We will test this hypothesis by asking: 1) Can pathogenic mutations in PKD1 or PKD2 disrupt non-canonical Wnt signaling pathway? 2) How the activation process of the PKD1/TRPP2 complex is modulated by the non-canonical Wnt pathways? And 3) Do these two pathways intersect in vivo? These questions will be addressed by complementary approaches in cell culture, zebrafish embryos, and the mouse. The proposed studies will help us understand fundamental properties of PKD1 and TRPP2 and their roles in cystogenesis. As the pathophysiological basis of ADPKD is unknown, these experiments will set the stage for the development of therapeutic strategies.

常染色体显性多囊性肾脏疾病（ADPKD）是最常见的遗传疾病之一。随着肾脏，肝脏和胰腺中上皮囊肿的发展，它影响了1000名美国人中的1个。在两个单独的基因PKD1和PKD2中，天然发生的突变是所有ADPKD病例中绝大多数（〜99％）的原因。 PKD1编码具有长细胞外域的大质膜蛋白，而PKD2编码TRP超家族的离子通道（目前命名为TRPP2）。我们和其他人表明，PKD1与TRPP2物理相互作用，形成将细胞外刺激与Ca2+涌入联系起来的离子通道复合物（PKD1/TRPP2）。但是，这些基因中的突变如何引起ADPKD仍然未知。与β-catenin无关的Wnt途径的缺陷（非官方WNT途径）也与囊肿发生有关。我们建议PKD1/TRPP2介导的信号传导与非典型WNT途径之间存在功能相互作用。我们将通过询问：1）PKD1或PKD2中的致病突变会破坏非典型的Wnt信号通路吗？ 2）PKD1/TRPP2复合物的激活过程如何由非规范WNT途径调节？ 3）这两个途径在体内是否相交？这些问题将通过细胞培养，斑马鱼胚胎和小鼠的互补方法来解决。拟议的研究将有助于我们了解PKD1和TRPP2的基本特性及其在囊肿发生中的作用。由于ADPKD的病理生理基础尚不清楚，因此这些实验将为发展治疗策略的发展奠定基础。