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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：
8670724
负责人：
Leonidas Tsiokas
金额：
$ 32.06万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8670724
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 biophysical properties 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.

常染色体显性多囊肾病（ADPKD）是最常见的遗传病之一。千分之一的美国人患有肾、肝和胰腺上皮囊肿。两个独立基因 PKD1 和 PKD2 中自然发生的突变是绝大多数 (~99%) ADPKD 病例的原因。 PKD1 编码具有长胞外结构域的大型质膜蛋白，而 PKD2 编码 TRP 超家族的离子通道（目前命名为 TRPP2）。我们和其他人已经证明 PKD1 与 TRPP2 物理相互作用，形成离子通道复合物 (PKD1/TRPP2)，将细胞外刺激与 Ca2+ 流入联系起来。然而，这些基因突变如何导致 ADPKD 仍不清楚。与 β-连环蛋白（非典型 Wnt 通路）无关的 Wnt 通路分支缺陷也与囊肿发生有关。我们认为 PKD1/TRPP2 介导的信号传导与非经典 Wnt 通路之间存在功能性相互作用。我们将通过以下问题来检验这一假设：1) PKD1 或 PKD2 的致病性突变是否会破坏非经典 Wnt 信号通路？ 2）非经典Wnt通路如何调节PKD1/TRPP2复合物的激活过程？ 3）这两条途径在体内是否交叉？这些问题将通过细胞培养、斑马鱼胚胎和小鼠的补充方法得到解决。拟议的研究将帮助我们了解 PKD1 和 TRPP2 的基本特性及其在囊肿发生中的作用。由于 ADPKD 的病理生理学基础尚不清楚，这些实验将为治疗策略的制定奠定基础。