Investigating long noncoding RNAs as regulators of the p53 pathway functions.

研究长非编码 RNA 作为 p53 通路功能的调节因子。

• 批准号: 9975189
• 负责人: Adam Schmitt
• 金额: $ 44.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975189
• 关键词: Affect; Applications Grants; Binding; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Disease; Engineering; Genetic Transcription; Goals; Health; Human; Molecular; Pathway interactions; Physiological; Physiological Processes; Prevalence; Protein p53; RNA Binding; Research; Role; TP53 gene; Therapeutic; Transcript; Transcriptional Regulation; Tumor Suppressor Proteins; Untranslated RNA; Work; genome-wide; macromolecule; mammalian genome; programs; response

ABSTRACT Long noncoding RNAs (lncRNAs) have emerged as pervasive features of the mammalian genome with recent annotations identifying >50,000 lncRNAs in humans. Despite their prevalence, few of these transcripts have been functionally characterized. While multiple lines of evidence point to roles for lncRNAs in chromatin and transcription regulation, rigorous definition of the physiological effects of these molecules remains rare. However, our recent work has identified an evolutionarily conserved physiological role for a lncRNA that binds p53, further demonstrating that lncRNAs contribute to critically important cellular processes. The realization that lncRNAs can bind p53 and modulate p53 function establishes a new paradigm for information input onto p53, one in which alterations in the transcriptional landscape of cells may inform global reprograming of p53 physiological responses. In this proposal, we will systematically examine the role of p53-bound lncRNAs in cellular stress responses. We will leverage recent technical advances in genome-wide transcription engineering by CRISPR to systematically modulate the expression of p53-bound lncRNA expression and examine the the physiological consequences. The long term goals of our lab are to: (i) identify the repertoire of long noncoding RNAs that participate p53-dependent physiological processes and (ii) characterize the molecular mechanisms of these molecules with the goal of (iii) understanding how lncRNAs affect human health and disease in order to modulate them for therapeutic gain. The research program outlined here represents the first steps aimed at achieving these goals.

抽象的 长期非编码RNA（lncRNA）已成为哺乳动物的普遍特征 基因组和最近的注释鉴定了人类中> 50,000个lncrnas。尽管他们的流行率 这些转录本中很少有功能表征。而多行的证据指向 LNCRNA在染色质和转录调节中的作用，生理的严格定义 这些分子的作用仍然很少。但是，我们最近的工作已经在进化上确定 结合p53的LNCRNA的保守生理作用，进一步证明了lncrnas 有助于至关重要的细胞过程。意识到lncrnas可以结合p53和 调节p53功能为信息输入p53建立了一个新的范式，其中一个范式 细胞转录格局的改变可能会为p53的全局重编程提供信息 生理反应。 在此提案中，我们将系统地检查p53结合的lncRNA在细胞中的作用 压力反应。我们将利用全基因组转录的最新技术进步 CRISPR的工程系统以系统地调节p53结合lncRNA表达的表达 并检查生理后果。 我们实验室的长期目标是：（i）确定长期非编码RNA的曲目 参与p53依赖性生理过程和（ii）表征了分子机制 这些分子的目标是（iii）了解lncRNA如何影响人类健康和疾病 为了调节它们以获取治疗收益。这里概述的研究计划代表了第一个 旨在实现这些目标的步骤。