Investigating the roles of lncRNAs in cancer and development

研究 lncRNA 在癌症和发育中的作用

• 批准号: 9266375
• 负责人: Andrea Ventura
• 金额: $ 41.96万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266375
• 关键词: Aging; Applications Grants; B-Cell Lymphomas; B-Lymphocytes; Biological; Biological Models; Biological Process; Biology; Cell Differentiation process; Code; Communities; Data; Development; Disease; Doxycycline; Ectopic Expression; Embryonic Development; Ensure; Epigenetic Process; Generations; Genetic; Genetic study; Genetically Engineered Mouse; Goals; Health; Hematopoiesis; Human; Human Genome; In Vitro; Individual; Investigation; Lead; Lymphocyte; Lymphomagenesis; Malignant Neoplasms; Modality; Molecular; Mus; Oncogenic; Orthologous Gene; Pathogenesis; Phase; Physiological; Play; Prognostic Marker; Property; Proteins; Public Health; RNA interference screen; Regulation; Research Proposals; Role; System; Testing; Therapeutic; Transgenic Organisms; Untranslated RNA; Work; aged; base; design; diagnostic biomarker; differential expression; experimental study; gain of function; high throughput screening; in vivo; innovation; insight; interdisciplinary approach; loss of function; mammalian genome; mouse model; novel; novel diagnostics; novel therapeutic intervention; public health relevance; screening; transcriptome; transcriptome sequencing; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Mammalian genomes are pervasively transcribed, but only a fraction of the transcribed RNAs appears to encode for proteins. Among the non-coding component of the transcriptome, long intergenic non-coding RNAs (lincRNAs) have recently been the subject of intense investigation due to their potential roles in cell differentiation, development, and disease. Although several lincRNAs have been proposed to play a role in the pathogenesis of human cancers, definitive experimental evidence is still missing and our understanding of the precise biological functions and modality of action of the vast majority of them is minimal or absent. Here we propose to investigate the potential roles of lincRNAs in the pathogenesis of Myc-driven B cell lymphomas. Our central hypothesis is that a subset of lincRNAs possesses oncogenic or tumor suppressive properties and that these lincRNAs contribute to lymphomagenesis. To test this hypothesis we are proposing a multidisciplinary approach that consists in a first high-throughput phase in which we aim to identify lincRNAs that are de-regulated during Myc-driven lymphomagenesis. Next, this set of lincRNAs will be subjected to in vitro and in vivo functional screens to identify those that can accelerate or impai tumor progression. Finally, the most promising candidates will be investigated through loss of function and gain of function experiments in genetically engineered mice. Our ultimate goals are to define the roles of these lincRNAs in tumorigenesis, determine their physiologic functions, and identify their mechanisms of action. We predict that the successful completion of the experiments described in this proposal will provide important insights into the biology of this important class of non-coding RNAs and will define their potential roles in tumorigenesis.

描述（由申请人提供）：哺乳动物基因组普遍转录，但只有一部分转录的RNA似乎编码蛋白质。在转录组的非编码组分中，长基因间非编码RNA（lincRNA）由于其在细胞分化、发育和疾病中的潜在作用而最近成为深入研究的主题。尽管已经提出了几种lincRNA在人类癌症的发病机制中发挥作用，但仍然缺少明确的实验证据，并且我们对它们中的绝大多数的精确生物学功能和作用方式的理解是最少的或不存在的。在这里，我们建议调查的潜在作用lincRNA的Myc驱动的B细胞淋巴瘤的发病机制。我们的中心假设是lincRNA的子集具有致癌或肿瘤抑制特性，并且这些lincRNA有助于淋巴瘤发生。为了验证这一假设，我们提出了一种多学科的方法，该方法包括第一个高通量阶段，在该阶段中，我们的目标是鉴定在Myc驱动的淋巴瘤发生过程中失调的lincRNA。接下来，将对这组lincRNA进行体外和体内功能筛选，以鉴定可以加速或影响肿瘤进展的那些。最后，最有希望的候选人将通过基因工程小鼠的功能丧失和功能获得实验进行研究。我们的最终目标是确定这些lincRNA在肿瘤发生中的作用，确定它们的生理功能，并确定它们的作用机制。我们预测，本提案中描述的实验的成功完成将为这类重要的非编码RNA的生物学提供重要的见解，并将定义它们在肿瘤发生中的潜在作用。