Mechanisms of Polycystin and Cilia Function in ADPKD

多囊蛋白和纤毛在 ADPKD 中的功能机制

• 批准号: 8857435
• 负责人: STEFAN SOMLO
• 金额: $ 36.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857435
• 关键词: Ablation; Adult; Affect; Animal Model; Antibodies; Autosomal Dominant Polycystic Kidney; Binding; Biological Assay; Cell Line; Cell model; Cells; Cilia; Complement; Complex; Cyst; Cystic kidney; Data; Development; Disease; Duct (organ) structure; Epithelial Cells; Equation; Fibronectin Receptors; Fibronectins; Gene Dosage; Gene Expression Profile; Gene Silencing; Genes; Genetic; Genetic Models; Genotype; Health; Human; In Vitro; Individual; Integrins; Kidney; Kidney Failure; Knock-out; Left; Ligands; Membrane; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Nephrons; PKD2 protein; Pathogenesis; Pathway interactions; Phenotype; Polycystic Kidney Diseases; Principal Investigator; Property; Proteins; Proteomics; Relative (related person); Role; Series; Severities; Signal Pathway; Signal Transduction; Staging; Structure; Time; Transgenic Organisms; Translations; base; bile duct; early onset; expectation; in vivo; inhibitor/antagonist; kinetosome; mouse model; mutant; novel; polycystic kidney disease 1 protein; preclinical efficacy; programs; recombinase; reconstitution; transcriptomics

DESCRIPTION (provided by applicant): The functional connection between human polycystic kidney diseases and cilia is based in part on the overlap between genes whose mutation results in kidney cyst formation and genes whose protein products are expressed in the cilia-basal body complex. The occurrence of a common phenotype, kidney cysts, following mutation in either of these classes of genes has led to a conceptual equation of cellular pathways affected by loss of polycystin-1 (PC1) or polycystin-2 (PC2) with those affected following loss of structurally intact cilia. This proposal is based on our novel observation that cyst formation following inactivation o either Pkd1 or Pkd2 is markedly slowed if structurally intact cilia are concomitantly ablated. This effect is present in adult onset and early developmental mouse models of both Pkd1 and Pkd2 and is independent of the genetic mechanism of cilia ablation. The findings provide genetic evidence for a pathway that is inhibited by the PC1/PC2 complex and that requires intact cilia to produce maximal cyst promoting signals in the absence of PC1/PC2-a Cilia Dependent Cyst Activating (CDCA) pathway. The objective of this proposal are to identify the components of the CDCA pathway. To achieve this objective, we will define the specific determinants of cyst progression whose activity following inactivation of polycystins is modulated by the presence or absence of intact cilia. We will use a highly correlated series of in vivo mouse models that subsume all stages of CDCA to investigate known and novel candidate CDCA pathways. We will complement these directed studies with transcriptomic and proteomic discovery approaches. We have identified integrin signaling as a candidate CDCA activity. We will explore the role of polycystins in integrin signaling in cilia and determine which components of this pathway are active in cilia. We will use gene knockdown in cells and conditional knockout models in mice to determine whether integrin signaling is a component of CDCA and if so, we will target it therapeutically to determine preclinical efficacy in ADPKD. The overall program offers two novel discoveries regarding the pathogenesis of ADPKD that each have substantial potential for translation.

描述（由申请人提供）：人类多囊肾病和纤毛之间的功能联系部分是基于导致肾囊肿形成的突变基因和在纤毛-基底体复合体中表达蛋白产物的基因之间的重叠。在这两类基因中的任何一类发生突变后，出现了一种常见的表型，即肾囊肿，这导致了一个概念方程，即在结构完整的纤毛丢失后，受多囊蛋白-1 （PC1）或多囊蛋白-2 （PC2）丢失影响的细胞通路。这一建议是基于我们的新观察，即如果同时切除结构完整的纤毛，则Pkd1或Pkd2失活后的囊肿形成明显减慢。这