Investigating the roles of lncRNAs in cancer and development

研究 lncRNA 在癌症和发育中的作用

基本信息

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
项目类别：
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

项目摘要

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，但只有一小部分转录的 RNA 似乎编码蛋白质。在转录组的非编码成分中，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，最近成为深入研究的主题。尽管已经提出几种 lincRNA 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，而且我们对其中绝大多数的精确生物学功能和作用方式的了解很少或根本不存在。在这里，我们建议研究 lincRNA 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 lincRNA 的一个子集具有致癌或肿瘤抑制特性，并且这些 lincRNA 有助于淋巴瘤的发生。为了检验这一假设，我们提出了一种多学科方法，该方法包括第一个高通量阶段，我们的目标是识别在 Myc 驱动的淋巴瘤发生过程中失调的 lincRNA。接下来，这组 lincRNA 将接受体外和体内功能筛选，以确定那些可以加速或阻碍肿瘤进展的 lincRNA。最后，最有希望的候选者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一类重要的非编码 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。