Sequence-specific Hybridization Capture for Discovery of Proteoform–lncRNA Interactions in Prostate Cancer

用于发现前列腺癌中 Proteoform-lncRNA 相互作用的序列特异性杂交捕获

基本信息

批准号：
10307993
负责人：
DAVID F. JARRARD
金额：
$ 38.86万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-04 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307993
关键词：
Aftercare Aggressive course Apoptosis Biological Biological Assay Biological Markers Blood capillaries Cells Cessation of life Chromatin Clinical Complex Databases Development Diagnosis Disease Disease Management Disease Progression Economics Evaluation Gene Expression Genetic Transcription Genomics Grant Growth HIV Human Immunoprecipitation Individual Indolent Informatics Intelligence MALAT1 gene MYC gene Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Messenger RNA Monitor Nature Neoplasm Metastasis Outcome Patients Peptides Phase Play Process Prognostic Marker Prostate-Specific Antigen Prostatic Neoplasms Proteins Proteomics Quality of life RNA RNA Processing RNA Splicing RNA purification RNA-Binding Proteins Regulation Research Personnel Resistance Role Sampling Signal Transduction Site Software Tools Solid Neoplasm System Techniques Technology Testing Time Tissue Sample Transcript Translations United States Untranslated RNA Variant Work angiogenesis c-myc Genes cancer cell cancer diagnosis design differential expression genomic RNA human tissue improved insight instrument men minimally invasive multiple data types new technology new therapeutic target novel patient derived xenograft model prognostic assays programs protein complex proteomic signature recruit scaffold success tool transcriptome sequencing tumor

项目摘要

Project Summary/Abstract Long noncoding RNAs (lncRNAs) are vital components of gene expression programs controlling cellular differentiation and function. lncRNAs act as scaffolds to recruit or sequester effector proteins. They may act in cis and trans at multiple genomic sites. lncRNAs modulate transcription, chromatin organization, RNA processing, and translation, and many questions remain unanswered regarding how they influence gene expression. Recent reviews have detailed several lncRNAs that play key roles in prostate cancer including regulation of processes in cancer cells such as proliferative signaling, replicative immortality, invasion and metastasis, evasion of growth suppressors, induction of angiogenesis and resistance to apoptosis. While much remains to be learned regarding the mechanisms of action involved in lncRNA function, it is abundantly clear that lncRNAs act in concert with associated proteins to carry out their roles. Distinguishing between aggressive and indolent prostate cancer is a major conundrum in cancer. In roughly one-third of the 140,000 intermediate grade cancers (Gleason 7) diagnosed annually, the disease follows a more aggressive course developing rapid progression of prostate specific antigen (PSA) after treatment and earlier metastasis and death. During the prior three-year grant period, we discovered several dozen lncRNAs that distinguish aggressive and indolent prostate cancers, of which four were validated using RT-qPCR. We also developed the HyPR-MS strategy to permit elucidation of specific RNA-protein interactomes. In this renewal proposal we seek to further develop and apply a suite of powerful new proteomics tools to study these and other prostate cancer-relevant lncRNAs and the proteins that associate with them, and use this capability to reveal important proteomic signatures to distinguish aggressive versus indolent prostate cancer. These studies will provide a novel and unprecedented view into the nature of the proteoform–lncRNA interactions that underlie lncRNA function. The delineation of differentially expressed lncRNAs and their associated proteins/proteoforms will provide insight into the biological mechanisms underlying disease progression and provide novel therapeutic targets for further development.

项目概要/摘要长非编码 RNA (lncRNA) 是控制细胞的基因表达程序的重要组成部分 lncRNA 充当招募或隔离效应蛋白的支架。多个基因组位点的顺式和反式 lncRNA 调节转录、染色质组织、RNA。加工和翻译，以及它们如何影响基因的许多问题仍未得到解答最近的评论详细介绍了几种在前列腺癌中发挥关键作用的lncRNA，包括癌细胞过程的调节，例如增殖信号、复制永生性、侵袭和转移、逃避生长抑制剂、诱导血管生成和抵抗细胞凋亡等。关于 lncRNA 功能的作用机制仍有待了解，目前已经非常清楚 lncRNA 与相关蛋白协同作用以发挥其作用。区分侵袭性前列腺癌和惰性前列腺癌是癌症中的一个主要难题。每年诊断出 140,000 例中级癌症 (Gleason 7) 中的三分之一，该疾病遵循治疗后前列腺特异性抗原（PSA）快速进展，并且在之前的三年资助期内，我们发现了数十个 lncRNA。区分侵袭性和惰性前列腺癌，其中四种通过 RT-qPCR 进行了验证。还开发了 HyPR-MS 策略来阐明特定的 RNA-蛋白质相互作用组。在这个更新提案中，我们寻求进一步开发和应用一套强大的新蛋白质组学工具来研究这些和其他前列腺癌相关的 lncRNA 以及与其相关的蛋白质，并使用它能够揭示重要的蛋白质组学特征，以区分侵袭性前列腺癌和惰性前列腺癌。这些研究将为蛋白质型 lncRNA 的性质提供新颖且前所未有的视角 lncRNA 功能背后的相互作用差异表达的 lncRNA 及其特征的描述。相关蛋白质/蛋白质形式将提供对疾病潜在生物学机制的深入了解进展并为进一步开发提供新的治疗靶点。