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：
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
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/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

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）：哺乳动物基因组被普遍转录，但只有一小部分转录的RNA似乎编码为蛋白质。在转录组的非编码成分中，由于其潜在的细胞分化，发育和疾病，由于其潜在的作用，因此最近已进行了严格研究的主题。尽管已经提出了几种LincrNA在人类癌症的发病机理中发挥作用，但仍缺少确定性的实验证据，我们对其中绝大多数的精确生物学功能和作用方式的理解是最小或缺失的。在这里，我们建议研究LincrNA在MYC驱动的B细胞淋巴瘤发病机理中的潜在作用。我们的中心假设是，一部分LincrNA具有致癌性或肿瘤抑制特性，并且这些LincrNA有助于淋巴作用。为了检验这一假设，我们提出了一种多学科方法，该方法是在第一个高通量阶段组成的，在该阶段中，我们旨在识别在MYC驱动的淋巴疗法期间被取消调节的lincRNA。接下来，这组LincrNA将受到体外和体内功能筛选，以识别那些可以加速或impai肿瘤进展的筛选。最后，将通过基因工程小鼠的功能丧失和功能实验的增益来研究最有希望的候选人。我们的最终目标是定义这些LincrNA在肿瘤发生中的作用，确定其生理功能并确定其作用机理。我们预测，该提案中描述的实验的成功完成将为这一重要的非编码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。