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

• 批准号: 10541119
• 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
• 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/10541119
• 关键词: Aftercare; Aggressive course; Apoptosis; Binding; 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; Invaded; Learning; 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; technology platform; tool; transcriptome sequencing; tumor

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.

项目总结/摘要 长链非编码RNA（lncRNA）是基因表达程序的重要组成部分， 分化和功能。lncRNA作为支架募集或隔离效应蛋白。他们可能会采取行动， 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，关于它们如何影响基因的许多问题仍然没有答案。 表情最近的综述详细介绍了几种在前列腺癌中起关键作用的lncRNA，包括 调节癌细胞中的过程，如增殖信号传导、复制永生、侵袭和 转移、逃避生长抑制因子、诱导血管生成和抗细胞凋亡。虽然大部分 关于lncRNA功能的作用机制仍有待了解，但很明显， lncRNA与相关蛋白协同发挥作用。 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。大致 在每年诊断的140，000例中级癌症（Gleason 7）中，有三分之一的人患有这种疾病， 治疗后前列腺特异性抗原（PSA）快速进展的更积极的过程， 早期转移和死亡。在前三年的资助期内，我们发现了几十种lncRNAs 区分侵袭性和惰性前列腺癌，其中四种使用RT-qPCR验证。我们 还开发了HyPR-MS策略，以允许阐明特定的RNA-蛋白质相互作用组。 在这项更新建议中，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和与它们相关的蛋白质，并使用这种 揭示重要的蛋白质组特征以区分侵袭性前列腺癌与惰性前列腺癌的能力。 这些研究将提供一个新的和前所未有的看法，蛋白质的性质-lncRNA lncRNA功能基础的相互作用。差异表达的lncRNA的描绘及其在 相关的蛋白质/蛋白质型将提供深入了解疾病的生物学机制 并为进一步开发提供新的治疗靶点。