The intersection of RNA biology and tumor biology

 描述(申请人提供)：门德尔实验室致力于RNA生物学和癌症生物学的前沿，研究非编码RNA的功能，非编码RNA在肿瘤发生中的作用，以及基于RNA的工具的应用，以阐明非编码RNA和肿瘤生物学。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，特别是在microRNA(MiRNA)途径上。我们在这一领域的早期工作表明，miRNAs是关键的致癌和肿瘤抑制网络的关键组成部分，包括MYC、KRAS和P53通路。我的实验室一直处于阐明miRNA在体内的功能并将这些发现转化为新的治疗方法的前沿，最引人注目的是我们证明了全身注射miRNAs有效地抑制了小鼠癌症模型的肿瘤发生，而没有毒性。我们还提高了对miRNA调控的理解，识别了受调控的miRNA生物发生和衰退的例子。展望未来，对于探索RNA生物学和肿瘤生物学的接口来说，这是一个特别重要和令人兴奋的时刻。在对miRNAs在癌症中的作用进行了十多年的研究后，我们对miRNAs如何在体内促进肿瘤发生的了解仍然令人惊讶地有限。因此，非常需要推导和分析新的体内miRNA功能增减模型。我们还了解到，miRNA成熟的扰动，无论是通过miRNA生物发生机制的组件突变，还是通过特定的miRNA调控途径的异常活性，都是人类恶性肿瘤的共同特征。然而，在癌症中miRNA成熟是如何被调控的仍然知之甚少。除了miRNA途径外，我们现在还知道存在数以千计的长非编码RNA(LncRNAs)，它们参与哺乳动物不同的细胞和发育功能。新出现的数据暗示了lncRNAs在癌症中的重要作用，但我们还处于了解其潜在机制的最早阶段。最后，强大的基于RNA的基因组编辑工具的出现为体内非编码RNA的功能分析提供了前所未有的机会。基于我们知识中的这些差距以及新的研究机会，我们下一阶段的研究将集中在1)利用新型的功能获得和丢失的小鼠模型分析miRNA在正常生理和体内癌症中的功能；2)研究miRNA在正常发育和肿瘤发生中的调节作用；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；以及4)应用基于CRISPR的基因组编辑来阐明细胞和动物中的非编码RNA功能以及发现和验证与恶性肿瘤相关的表型的新调节因子。我的实验室处于独特的位置，可以综合这些研究领域，从而继续我们在非编码RNA和癌症生物学社区中持续生产力和领先地位的记录。

 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.