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Molecular modulators of polycystin signaling

多囊蛋白信号传导的分子调节剂

基本信息

批准号：
10356036
负责人：
STEFAN SOMLO
金额：
$ 42.4万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356036
关键词：
ATAC-seq Address Adult Affect Affinity Chromatography Antisense Oligonucleotides Apoptosis Attenuated Autosomal Dominant Polycystic Kidney Biological Assay Biology Cell Culture System Cell Culture Techniques Cell Cycle Cell Line Cell Proliferation Cells ChIP-seq Chromatin Chromatin Structure Cilia Complex Consensus Cyst Data Dialysis procedure Disease Down-Regulation GLIS2 gene Gene Dosage Genes Genetic Genetic Diseases Genetic Transcription Genotype Growth In Vitro Inherited Investigation Kidney Kidney Diseases Knowledge Maps Modeling Molecular Mutation Oxidative Phosphorylation PKD2 protein Pathogenesis Pathway interactions Patients Polycystic Kidney Diseases Post-Translational Protein Processing Pre-Clinical Model Property Proteins Proteolytic Processing Renal function Research Resolution Ribosomes Role Signal Pathway Signal Transduction Time Tissues Transgenic Organisms Translating Transplantation Transposase Up-Regulation Vitelliform macular dystrophy base differential expression dosage early onset expectation field study human disease improved in vitro Model in vivo in vivo Model innovation mouse model mutant novel novel therapeutics optimal treatments overexpression polycystic liver disease programs targeted treatment therapeutic target trafficking transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that results from mutations in either of two proteins, polcysytin-1 (PC1) or polycystin-2 (PC2). More than two decades have passed since the genes encoding these proteins were discovered and there has been significant progress in understanding the functions of polycystins and their associated disease. Nonetheless, there remain substantial gaps in knowledge and lack of consensus about the precise functions of PC1 or PC2 and the mechanisms of ADPKD. Resolution of these gaps is of great significance given our expectation that optimal therapies for ADPKD are best developed based on the fundamental understanding of polycystin function in the mammalian kidney. Much of the current mechanistic understanding of polycystin function is based on studies of candidate pathways drawn from amongst known cellular mechanisms associated with functions such as differentiation, proliferation, transport and signaling. The lack of coalescence toward an interrelated unifying functional pathway in polycystin biology and the persistence of gaps in understanding of in vivo polycystin function despite extensive investigation suggests that the critical components of the most proximal polycystin signaling cascade have yet to be identified. Indeed, the polycystins were discovered as complex, entirely novel proteins and it stands to reason that they may function in a signaling pathway that is not among those that are currently well understood or studied. We made use of this concept in by applying an unbiased in vivo transcriptomic study using Translating Ribosome Affinity Purification (TRAP) RNASeq. From this, we identified upregulation of cell cycle and down regulation of oxidative phosphorylation as key pathways alterations in vivo. Among these, we found genotype dependent upregulation of a cilia associated transcription factor, Glis2, not previously considered to function in polycystin signaling or ADPKD pathogenesis. We made double mutants of Pkd1 with Glis2 in early onset and adult models and found Glis2 dosage-dependent rescue of cyst formation in both. Based on these findings we propose that Glis2 is a candidate for a downstream effector of PC1 function that is critical for cyst progression in ADPKD. In this study, we will determine the in vivo mechanism of action of Glis2 and establish its effects on cyst cell proliferation, apoptosis and ADPKD due to Pkd2. We will determine whether Glis2 is a target for therapy through both genetic and pharmacotherapeutic studies. We will assess whether in vivo genotype dependent transcriptional changes we have identified are similarly extended to cell culture systems with Pkd mutant genotypes. We will also evaluate the functional properties of Glis2 protein in Pkd mutant cell lines. In aggregate, these studies open a new direction of investigation for polycystin signaling and ADPKD pathogenesis.