The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
基本信息
- 批准号:9125799
- 负责人:
- 金额:$ 77.2万
- 依托单位:
- 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:2015-08-12 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAreaBiogenesisBiologyCancer BiologyCancer ModelCause of DeathCell modelCellsClustered Regularly Interspaced Short Palindromic RepeatsCommunitiesDataDerivation procedureDevelopmentDiseaseHealthHumanInvestigationKRAS2 geneKnowledgeLaboratoriesLeadershipLearningMalignant NeoplasmsMammalsMicroRNAsMusMutationOncogenicPathway interactionsPhasePhenotypePhysiologyPlayPositioning AttributeProcessProductivityRNARegulationRegulatory PathwayResearchRoleStagingTP53 geneTimeToxic effectTranslatingTumor BiologyTumor Suppressor ProteinsUnited StatesUntranslated RNAWorkbasegenome editingin vivoin vivo Modelloss of functionmouse modelnovelnovel therapeutic interventiontooltumorigenesis
项目摘要
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的工具在阐明非编码RNA和肿瘤生物学中的应用。我们对理解非编码RNA在癌症中的作用做出了重大贡献,特别关注microRNA(miRNA)途径。我们在这一领域的早期工作表明,miRNA是关键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体内miRNA功能的最前沿,并将这些发现转化为新的治疗方法,最值得注意的是通过我们的证明,miRNA的全身递送有效地抑制了小鼠癌症模型中的肿瘤发生,而没有毒性。我们还提高了我们对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,这是探索RNA生物学和肿瘤生物学界面的一个特别重要和令人兴奋的时刻。经过十多年对miRNAs在癌症中的作用的研究,我们对miRNAs如何促进体内肿瘤发生的理解仍然非常有限。因此,非常需要推导和分析新的miRNA功能获得和丧失的体内模型。我们还了解到,通过miRNA生物发生机制的组分突变或通过特定miRNA调控途径的异常活性,miRNA成熟的扰动是人类恶性肿瘤的共同特征。然而,对于miRNA成熟在癌症中是如何被调控的,我们仍然知之甚少。除了miRNA途径,我们现在知道存在数千种长的非编码RNA(lncRNA),它们参与哺乳动物的多种细胞和发育功能。新出现的数据暗示lncRNA在癌症中的重要作用,但我们正处于了解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。基于这些知识上的空白和新的研究机会,我们下一阶段的研究将集中在1)使用新的功能获得和功能丧失小鼠模型分析miRNA在正常生理和体内癌症中的功能; 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在正常生理学和癌症中的功能;以及4)CRISPR的应用-基于基因组编辑,以阐明细胞和动物中的非编码RNA功能,并发现和验证恶性相关表型的新型调节因子。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和癌症生物学领域的持续生产力和领导力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joshua T Mendell其他文献
Tumors line up for a letdown
肿瘤排队等待失望。
- DOI:
10.1038/ng0709-768 - 发表时间:
2009-07-01 - 期刊:
- 影响因子:29.000
- 作者:
Joshua T Mendell - 通讯作者:
Joshua T Mendell
Joshua T Mendell的其他文献
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{{ truncateString('Joshua T Mendell', 18)}}的其他基金
The role of long noncoding RNA CRNDE in normal physiology and cancer
长链非编码RNA CRNDE在正常生理和癌症中的作用
- 批准号:
10715065 - 财政年份:2023
- 资助金额:
$ 77.2万 - 项目类别:
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:
8953055 - 财政年份:2015
- 资助金额:
$ 77.2万 - 项目类别:
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:
10213661 - 财政年份:2015
- 资助金额:
$ 77.2万 - 项目类别:
Functional Evaluation of microRNAs in Pancreatic Neoplasia
microRNA 在胰腺肿瘤中的功能评估
- 批准号:
8464662 - 财政年份:2013
- 资助金额:
$ 77.2万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
7915972 - 财政年份:2009
- 资助金额:
$ 77.2万 - 项目类别:
Functional Evaluation of microRNAs in Pancreatic Neoplasia
microRNA 在胰腺肿瘤中的功能评估
- 批准号:
7651550 - 财政年份:2009
- 资助金额:
$ 77.2万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8026614 - 财政年份:2007
- 资助金额:
$ 77.2万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8712397 - 财政年份:2007
- 资助金额:
$ 77.2万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8578048 - 财政年份:2007
- 资助金额:
$ 77.2万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
7766253 - 财政年份:2007
- 资助金额:
$ 77.2万 - 项目类别:
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