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: 8760845
• 负责人: Andrea Ventura
• 金额: $ 43.24万
• 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/8760845
• 关键词: Age; 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; Functional RNA; Gene Expression Profile; Generations; Genetic; 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; Regulation; Research Proposals; Role; System; Testing; Therapeutic; Transgenic Organisms; Work; aged; base; design; 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; research study; screening; 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(申请人提供)：哺乳动物基因组被广泛转录，但似乎只有一小部分转录的RNA编码蛋白质。在转录组的非编码成分中，长基因间非编码RNA(LincRNAs)因其在细胞分化、发育和疾病中的潜在作用而成为近年来研究的热点。尽管已经提出了几个lincRNAs在人类癌症的发病机制中发挥作用，但仍然缺乏明确的实验证据，我们对其中绝大多数的确切生物学功能和作用方式的了解很少或缺乏。在此，我们建议研究lincRNAs在Myc驱动的B细胞淋巴瘤发病机制中的潜在作用。我们的中心假设是，lincRNAs的一个子集具有致癌或肿瘤抑制特性，并且这些lincRNAs有助于淋巴肿大。为了验证这一假设，我们提出了一个多学科的方法，包括第一个高通量阶段，在这个阶段，我们的目标是识别在Myc驱动的淋巴瘤发生过程中去调控的lincRNAs。接下来，这组lincRNAs将在体外和体内进行功能筛选，以确定哪些可以促进或损害肿瘤的进展。最后，将通过基因工程小鼠的功能丧失和功能获得实验来研究最有希望的候选者。我们的最终目标是确定这些lincRNAs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，这项提案中描述的实验的成功完成将为这一重要类别的非编码RNA的生物学提供重要的见解，并将确定它们在肿瘤发生中的潜在作用。