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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。

基本信息

批准号：
10219299
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
项目类别：
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

项目摘要

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.

摘要长链非编码RNA（lncRNA）已经成为哺乳动物细胞的普遍特征，最近的注释鉴定了人类中> 50，000个lncRNA的基因组。尽管它们普遍存在，这些转录物中很少有功能上的特征。虽然多条证据表明 lncRNA在染色质和转录调节中的作用，严格定义了生理上的这些分子的影响仍然罕见。然而，我们最近的研究发现，结合p53的lncRNA的保守生理作用，进一步证明lncRNA 对重要的细胞过程都有贡献。lncRNA可以结合p53，调节p53功能为p53上的信息输入建立了一个新的范例，其中之一是，细胞转录水平的改变可能会影响p53的整体重编程生理反应。在这个建议中，我们将系统地研究p53结合的lncRNA在细胞中的作用，应激反应我们将利用全基因组转录的最新技术进展通过CRISPR工程化以系统地调节p53结合的lncRNA表达的表达并检查其生理后果。我们实验室的长期目标是：（i）确定长非编码RNA的库，参与p53依赖的生理过程和（ii）表征的分子机制，这些分子的目标是（iii）了解lncRNA如何影响人类健康和疾病，以便调节它们以获得治疗效果。这里概述的研究计划代表了第一个旨在实现这些目标的措施。