权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The RNA structural code underlying pathological regulation of RNA splicing in metastasis

转移中RNA剪接病理调控的RNA结构密码

基本信息

批准号：
10358636
负责人：
Hani Goodarzi
金额：
$ 35.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358636
关键词：
Address Alternative Splicing Awareness Binding Binding Sites Biochemical Bioinformatics Biological Assay Biology Breast Cancer Patient Breast cancer metastasis Clinical Code Collaborations Communities Complex Comprehensive Cancer Center Computational Biology Dissection Elements Enhancers Event Exons Family Genetic Transcription Genomics Goals Human In Vitro Knowledge Malignant Neoplasms Measurement Mediating Messenger RNA Metastatic breast cancer Methodology Modeling Molecular Mus Mutation Neoplasm Metastasis Nonmetastatic Pathologic Pathway interactions Patients Play Positioning Attribute Post-Transcriptional Regulation Protein Isoforms Public Health RNA RNA Processing RNA Sequences RNA Splicing RNA-Binding Proteins Regulation Regulatory Element Regulatory Pathway Regulon Reporter Research Role Sampling Small Nuclear Ribonucleoproteins Structure Survival Analysis Trans-Splicing Transcript Up-Regulation Work Xenograft procedure base breast cancer progression cancer cell clinically relevant computer framework experimental study in silico in vivo innovation interdisciplinary approach knock-down lung colonization mouse model novel overexpression patient derived xenograft model programs promoter shape analysis targeted treatment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Widespread aberrant splicing is now considered a hallmark of cancer, and many of the resulting transcript isoforms have been functionally implicated in tumorigenesis. However, the underlying regulatory pathways that govern RNA splicing and the extent to which they play a role in cancer progression remain largely unknown. Due to our limited knowledge of splicing regulation, we cannot solely rely on annotated pathways to study changes in transcript isoforms. Moreover, bioinformatic strategies that are often used in discovering transcriptional regulatory pathways often fail to capture the complexities of post-transcriptional regulation. For example, common methodologies for cis-element discovery focus on sequence alone and largely ignore the integral role of the RNA structural code in splicing. To address this challenge, we have developed a computational framework that performs context-aware analysis of alternative splicing events to identify known and novel regulators of RNA processing. Using this approach, we have discovered and partly characterized a previously unknown RNA structural splicing enhancer (SSE) that drives aberrant splicing in highly metastatic breast cancer. We have identified the associated RNA-binding protein that serves as the trans factor that interacts with this novel SSE. We have shown that this pathway drives metastatic progression in xenograft mouse models and that its activity is strongly associated with poor survival in patients. In this proposal, we will build on this previous work to (i) perform a detailed dissection of this non-canonical regulatory pathway of alternative splicing, its underlying molecular machinery, and its governing RNA structural code; (ii) evaluate the contribution of this pathway to breast cancer progression; and (iii) establish the clinical relevance of this pathway and its regulon to cancer.

项目总结