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Integrative approach to studying LncRNA functions

研究 LncRNA 功能的综合方法

基本信息

批准号：
10119971
负责人：
Xiaobo Zhou
金额：
$ 30.58万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10119971
关键词：
Address Affect Alternative Splicing Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Award Binding Sites Bioinformatics CYP21A2 gene Cellular Stress Cleaved cell Colon Adenocarcinoma Computer software Data Data Set Disease Enzymes Epigenetic Process Event GPR3 gene Gene Expression Regulation Genes Genetic Transcription Genome Glioma Impairment Introns Investigation Malignant Neoplasms Maps Medicine Melanoma Cell Methods MicroRNAs Modeling Modification Neoplasm Metastasis Oncogenic Open Reading Frames Parents Pathogenesis Pathogenicity Play Porifera Production Protein Isoforms Proteins RNA RNA Editing RNA Splicing Resources Role Signal Transduction Single Nucleotide Polymorphism Site Structure Survival Analysis System Systems Biology Therapeutic Transcript United States National Institutes of Health Untranslated RNA Work amyloid precursor protein processing annotation system base beta-site APP cleaving enzyme 1 bioinformatics tool cohort epigenetic regulation gamma-Aminobutyric Acid improved insight multidisciplinary multiple omics nervous system disorder next generation novel overexpression predictive modeling prognostic tool transcriptome sequencing transcriptomics tumor

项目摘要

Supplementary to the parent R01GM123037 “Integrative approach to studying LncRNA functions” The recent studies showed that lncRNAs were involved in many neurological diseases such as Alzheimer's disease (AD). First, lncRNAs impact AD pathogenesis because of their diverse functional effects from the epigenetic regulation. For example, β-site amyloid precursor protein cleaving enzyme-1 antisense transcript (BACE1-AS) is the lncRNA transcribed from the opposite strand of β -site APP cleaving enzyme-1 (BACE1) locus. Cell stress increased BACE1-AS levels, which in turn stimulates BACE1 expression, which could enhance APP processing and Ab1-42 production. Elevated Ab1-42 levels can further promote BACE1-AS overexpression and the APP processing cascade in a feedforward manner. Second, accumulating evidence shows that microRNAs play a critical role in the pathogenesis of AD. From the fact that ~ 90% of the SNPs associated with diseases are located in non-coding regions and lncRNA plays a role as a sponge of miRNAs, RNA-level editing, which has the similar effect as the single nucleotide variant in lncRNA, can result in aberrant gene expression regulation in AD. Third, another pathogenic post-transcriptional modification in lncRNA is the alternative splicing (AS). 17A mapped in intron 3 of G-protein-coupled receptor 51 gene (GPR51) undergoes AS. 17A lncRNA is upregulated in AD compared with control and AS event in 17A impairs the GABA B signaling, enhance Aβ secretion. The role and functions of the known lncRNAs have been accumulated. However, there is no deep functional annotation of post-transcriptionally modified lncRNAs that have RNA- editing or alternative splicing events in the AD. Therefore, there is an urgent need to develop new tools for analyzing the potential functional impact of the post-transcriptionally modified lncRNA systemically in the AD genome and predict their regulatory mechanisms. Here, we propose to develop an integrated system for transcriptomic sequencing data-based functional annotation of post-transcriptional modification events of lncRNAs in AD based on the AD sequencing data from ADSP consortium and other NIH controlled AD data sets. Our multidisciplinary team proposed the following aims: (1) We will develop functional mechanism prediction of lncRNAs' RNA-editing events through investigating the gain/loss of the binding sites of miRNAs, which targeting AD genes (we integrated ~ 1,500 AD genes.), due to RNA-editing with checking the expressional impact between RNA-editing +/- groups and studying the changed relative energy of lncRNA secondary structures. (2) We will develop functional mechanism prediction of lncRNAs' AS events through identifying AD-specific/associated AS events in lncRNAs, correlated lncRNA expressions with AD genes' AS isoforms, investigating the gain/loss of miRNA binding sites due to AS event, and SNP/SV-induced AS events. Our study will be focused on AD-related lncRNAs to identify epigenetic impact of these on AD genes and AD pathogenic mechanisms. This supplementary is within the scope of parent R01GM123037 where we proposed to develop Bioinformatics tools to study lncRNA functions for cancer.

补充父号R01GM123037《综合方法研究LncRNA功能》