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ESRP regulated alternative splicing in EMT/MET and kidney development

ESRP 调节 EMT/MET 和肾脏发育中的选择性剪接

基本信息

批准号：
8527305
负责人：
Thomas W Bebee
金额：
$ 4.92万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527305
关键词：
Address Alternative Splicing Biological Models Cell Communication Cell Differentiation process Cell Polarity Cell physiology Cells Cytoskeleton Development Disease Duct (organ) structure Ductal Epithelium Epithelial Epithelial Cells Epithelium Event Exons Genes Genetic Transcription Human Individual Kidney Kidney Glomerulus Knock-out Laboratories Maintenance Mediating Mesenchyme Metanephric Diverticulum Methodology Mus Pathway interactions Pattern Phenotype Polyadenylation Population Process Proteins Proteome Proteomics RNA Sequences RNA Splicing Regulation Renal tubule structure Role Spliced Genes Structure System Testing Tissue-Specific Splicing Transcript Tubular formation Work cell growth cell type epithelial to mesenchymal transition genetic regulatory protein in vivo insight migration nephrogenesis post-doctoral training programs protein function public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): An important mechanism to increase proteome diversity is through the process of alternative splicing (AS), wherein individual gene transcripts can be processed to generate functionally distinct proteins, a phenomenon identified in nearly all multi-exon human genes. While most known splicing regulatory proteins are ubiquitously expressed, a subset of tissue specific splicing regulators that govern global splicing regulatory networks (SRN) have been identified. Our laboratory has identified the cell type-specific epithelial splicing regulatory proteins (ESRP1 and ESRP2) that regulate splicing of gene transcripts encoding proteins involved in the maintenance of epithelial cell differentiation and function. The process of epithelial to mesenchymal transition (EMT) and the reverse process of MET have been extensively studied at the transcriptional level, while only recently has the impact of alternative splicing during these processes been evaluated. The ESRPs are primary regulators of AS during the EMT, where a dramatic reduction in ESRP1 and ESRP2 is observed compared to only modest changes in expression of other splicing regulators. Notably, genes regulated at the level of transcription and A encode proteins that function in common pathways that impact EMT, but the specific genes altered at the transcriptional and AS levels do not overlap, emphasizing the importance of alternative splicing as an additional layer of regulation involved in cellular reprogrammin during EMT. Epithelial cell differentiation and MET conversions are functionally conserved mechanisms important for normal development and can be clearly observed in the formation of the kidney, where the ESRPs are expressed. Identification of the SRN mediated by ESRP will be crucial in understanding the mechanism of EMT/MET conversions and lend insight into these processes during normal development and disease. We hypothesize that ESRP driven alternative splicing events are essential in the proper regulation of epithelial cell differentiation and function, as well as the process of MET in normal kidney development and patterning. To test the role of the Esrps in kidney development we will utilize Cre-mediated conditional knockouts for the Esrps to evaluate: 1) Esrp function and splicing regulation during epithelial cell differentiation/specification in ureteric bud branching and formation of collecting duct epithelial cells and 2) Esrp function and splicing regulaton during MET in the formation of renal tubular cells from the cap mesenchyme. To address the impact of Esrp loss in kidney development and regulation of a SRN in vivo we will analyze kidneys at the histological level and at the level of alternative splicing and polyadenylation using state-of-the-art high throughput RNA sequencing methodologies.

描述（由申请人提供）：增加蛋白质组多样性的一个重要机制是通过选择性剪接（AS）过程，其中单个基因转录物可以被加工以产生功能不同的蛋白质，这一现象几乎在所有多外显子人类基因中都有发现。虽然大多数已知的剪接调节蛋白是普遍表达的，但已经确定了控制全球剪接调节网络（SRN）的组织特异性剪接调节蛋白子集。我们实验室已经鉴定出