Project 3: Defining the biologic role and therapeutic implications of lncRNA in multiple myeloma

项目 3：定义 lncRNA 在多发性骨髓瘤中的生物学作用和治疗意义

• 批准号: 10555733
• 负责人: KENNETH C. ANDERSON
• 金额: $ 31.35万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555733
• 关键词: Animal Model; Area; Automobile Driving; Back; Behavior; Biological; Biological Models; Bone Marrow; Cell Communication; Cell Line; Cell Survival; Cells; Chromatin; Classification; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; DNA-Protein Interaction; Dana-Farber Cancer Institute; Data; Data Set; Dependence; Development; Disease; Drug resistance; Enzymes; Epigenetic Process; Frequencies; Funding; Genes; Genetic; Genetic Transcription; Genomics; Human; Human Genome; In Vitro; Left; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Multiple Myeloma; Oligonucleotides; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Probability; Process; Proliferating; Proteins; RNA; Reporting; Research; Ribonucleoproteins; Risk; Risk Marker; Role; Span 80; Specificity; Stromal Cells; Techniques; Therapeutic; Therapeutic Agents; Transcriptional Regulation; Translations; Untranslated RNA; Validation; bench to bedside; c-myc Genes; cancer genomics; cell growth; clinical application; differential expression; epigenomics; flexibility; gain of function; gene regulatory network; improved; in vivo; in vivo Model; inhibitor; lipid biosynthesis; loss of function; neoplastic cell; next generation; novel; novel therapeutics; outcome prediction; pre-clinical; predict clinical outcome; prognostic significance; protein B; response; scaffold; small molecule; small molecule inhibitor; targeted agent; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; translational therapeutics

Project Summary – Project 3 Dana-Farber Cancer Institute Our longstanding focus has been to understand the multiple myeloma (MM)-bone marrow stromal cell interaction. We have utilized integrated genomic and epigenomic analysis and our in vitro and in vivo models of MM cell in the bone marrow (BM) milieu to identify molecular targets and pathways supporting myeloma cell growth, survival, and drug resistance, and implement effective molecularly-based therapies with dramatic effects on the survival of MM patients. During the current funding period, we identified and validated gene regulatory networks and feed-forward loops controlling gene transcription and driving disease behavior and then evaluated targeted agents. In the process we identified the noncoding RNA (lncRNA) networks in MM. One of the emerging areas of research has been the recent advances highlighting the functional significance of lncRNAs) that span > 80% of the human genome. These RNA molecules control a variety of cellular and molecular functions via mechanisms that are yet not well described. We have previously described the aberrant lncRNA landscape in MM and reported the significant role of aberrant lncRNAs as an independent risk predictor for clinical outcome, providing the rationale to further investigate biological and molecular activity of lncRNAs in MM. We hypothesize that dysregulated lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with the potential to serve as therapeutic targets. In this project, our robust human MM model systems will be used to stringently validate the role of novel lncRNAs (Sp. Aim 1) identified to be of biologic/prognostic significance; and develop single and combination therapies directed against these clinically and biologically relevant novel lncRNAs (Sp. Aim 2). Leveraging our genomic and transcriptomic data, the proposed studies will define the functional landscape of lncRNAs in MM and their impact on the disease pathobiology, with the potential of developing novel translational therapies for the treatment of MM patients.

项目摘要 – 项目 3 丹纳法伯癌症研究所 我们长期以来的重点是了解多发性骨髓瘤 (MM) - 骨髓基质细胞 相互作用。我们利用了整合的基因组和表观基因组分析以及我们的体外和体内模型 骨髓 (BM) 环境中的 MM 细胞可识别支持骨髓瘤细胞的分子靶标和途径 生长、存活和耐药性，并实施有效的分子疗法，效果显着 MM 患者的生存情况。在当前资助期间，我们确定并验证了 控制基因转录和驱动疾病的基因调控网络和前馈回路 行为，然后评估目标代理。在此过程中，我们鉴定了非编码RNA MM 中的 (lncRNA) 网络。新兴研究领域之一是最新进展 强调了 lncRNA 的功能意义），其覆盖超过 80% 的人类基因组。这些RNA 分子通过尚不完善的机制控制各种细胞和分子功能 描述的。我们之前描述了 MM 中异常的 lncRNA 景观，并报告了显着的 异常 lncRNA 作为临床结果的独立风险预测因子的作用，为 进一步研究 lncRNA 在 MM 中的生物学和分子活性。我们假设失调 lncRNA 通过控制多个基因的能力显着影响 MM 的病理学，并具有潜在的潜力 作为治疗靶点。在这个项目中，我们强大的人类 MM 模型系统将用于严格 验证已确定具有生物学/预后意义的新型 lncRNA（Sp. Aim 1）的作用；并发展 针对这些临床和生物学相关的新型 lncRNA 的单一和组合疗法 （具体目标 2）。利用我们的基因组和转录组数据，拟议的研究将定义功能 MM 中 lncRNA 的概况及其对疾病病理学的影响，具有开发潜力 用于治疗 MM 患者的新型转化疗法。