The intersection of RNA biology and tumor biology

RNA生物学与肿瘤生物学的交叉点

• 批准号: 9125799
• 负责人: Joshua T Mendell
• 金额: $ 77.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-12 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125799
• 关键词: Animal Model; Animals; Area; Biogenesis; Biology; Cancer Biology; Cancer Model; Cause of Death; Cell model; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Data; Derivation procedure; Development; Disease; Health; Human; Investigation; KRAS2 gene; Knowledge; Laboratories; Leadership; Learning; Malignant Neoplasms; Mammals; MicroRNAs; Mus; Mutation; Oncogenic; Pathway interactions; Phase; Phenotype; Physiology; Play; Positioning Attribute; Process; Productivity; RNA; Regulation; Regulatory Pathway; Research; Role; Staging; TP53 gene; Time; Toxic effect; Translating; Tumor Biology; Tumor Suppressor Proteins; United States; Untranslated RNA; Work; base; genome editing; in vivo; in vivo Model; loss of function; mouse model; novel; novel therapeutic intervention; tool; tumorigenesis

 DESCRIPTION (provided by applicant): The Mendell laboratory works at the leading-edge of RNA biology and cancer biology, investigating noncoding RNA functions, the roles of noncoding RNAs in tumorigenesis, and the application of RNA-based tools to elucidate noncoding RNA and tumor biology. We have made major contributions to our understanding of the roles of noncoding RNAs in cancer, with a particular focus on the microRNA (miRNA) pathway. Our early work in this area demonstrated that miRNAs function as critical components of key oncogenic and tumor suppressor networks, including the MYC, KRAS, and p53 pathways. My laboratory has been at the forefront of elucidating miRNA functions in vivo and translating these findings into novel therapeutic approaches, most notably through our demonstration that systemic delivery of miRNAs potently suppresses tumorigenesis in mouse cancer models without toxicity. We have also advanced our understanding of miRNA regulation, identifying examples of regulated miRNA biogenesis and decay. Looking ahead, this is a particularly important and exciting time for exploring the interface of RNA biology and tumor biology. After more than a decade of research into the roles of miRNAs in cancer, our understanding of how miRNAs contribute to tumorigenesis in vivo is still surprisingly limited. There is thus a great nee for the derivation and analysis of novel in vivo models of miRNA gain- and loss-of-function. We have also learned that perturbations of miRNA maturation, either through mutations in components of the miRNA biogenesis machinery or through aberrant activity of specific miRNA regulatory pathways, are a common feature of human malignancies. Nevertheless, precisely how miRNA maturation is regulated in cancer remains poorly understood. Beyond the miRNA pathway, we now know of the existence of thousands of long noncoding RNAs (lncRNAs) that participate in diverse cellular and developmental functions in mammals. Emerging data implicate an important role for lncRNAs in cancer, but we are at the earliest stages of understanding the underlying mechanisms. Finally, the emergence of powerful RNA-based tools for genome editing has provided unprecedented opportunities for functional analysis of noncoding RNAs in vivo. Based on these gaps in our knowledge and new research opportunities, the next phase of our research will focus on 1) the analysis of miRNA functions in normal physiology and cancer in vivo using novel gain- and loss-of-function mouse models; 2) investigation of the regulation of miRNA processing in normal development and tumorigenesis; 3) elucidation of lncRNA functions in normal physiology and cancer using cellular and animal models; and 4) application of CRISPR-based genomic editing to illuminate noncoding RNA functions in cells and animals and to discover and validate novel regulators of malignancy-associated phenotypes. My laboratory is uniquely positioned to synthesize these areas of research and thereby continue our track record of sustained productivity and leadership within the noncoding RNA and cancer biology communities.

 描述（由申请人提供）：Mendell 实验室处于 RNA 生物学和癌症生物学的前沿，研究非编码 RNA 功能、非编码 RNA 在肿瘤发生中的作用，以及应用基于 RNA 的工具来阐明非编码 RNA 和肿瘤我们在理解非编码 RNA 在癌症中的作用方面做出了重大贡献，特别关注 microRNA (miRNA) 途径，我们在该领域的早期工作证明了 miRNA 的功能。关键致癌和肿瘤抑制网络的关键组成部分，包括 MYC、KRAS 和 p53 途径我们还加深了对 miRNA 调控的理解，确定了受调控的 miRNA 生物发生和衰变的例子，展望未来，这是一个特别重要且令人兴奋的探索时刻。 RNA 生物学和肿瘤生物学的交叉点 经过十多年对 miRNA 在癌症中的作用的研究，我们对 miRNA 如何促进体内肿瘤发生的了解仍然非常有限，因此非常需要推导和分析。我们还了解到，通过 miRNA 生物发生机制的成分突变或通过特定 miRNA 调控途径的异常活性，对 miRNA 成熟的干扰是一种常见的情况。然而，对于癌症中 miRNA 成熟的具体调控机制仍知之甚少。除了 miRNA 通路之外，我们现在还知道存在数千种参与哺乳动物不同细胞和发育功能的长链非编码 RNA (lncRNA)。新出现的数据表明lncRNA在癌症中发挥着重要作用，但我们仍处于了解其潜在机制的最初阶段。最后，基于RNA的强大基因组编辑工具的出现为非编码功能分析提供了前所未有的机会。基于我们的知识差距和新的研究机会，我们下一阶段的研究将集中于 1) 使用新型功能获得和丧失功能的小鼠来分析体内正常生理和癌症中的 miRNA 功能。 2) 研究正常发育和肿瘤发生中 miRNA 加工的调节；3) 使用细胞和动物模型阐明 lncRNA 在正常生理和癌症中的功能；4) 应用基于 CRISPR 的基因组编辑来阐明非编码 RNA我的实验室具有独特的优势，可以综合这些研究领域，从而继续我们在非编码 RNA 和癌症生物学界的持续生产力和领导地位。