The role of lncRNAs in P450-mediated drug metabolism and drug-induced liver injury

lncRNA在P450介导的药物代谢和药物性肝损伤中的作用

• 批准号: 10371142
• 负责人: XIAO-BO ZHONG
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371142
• 关键词: Address; Binding; Cytochrome P450; Enzymes; Epigenetic Process; Exposure to; Feedback; Gene Expression; Gene Expression Regulation; Genes; Homeostasis; In Vitro; Knowledge; Liver; Liver Regeneration; Mediating; Molecular; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predictive Factor; Predisposition; Process; Regulation; Response Elements; Role; Transcriptional Regulation; Treatment Efficacy; Untranslated RNA; Work; adverse drug reaction; chromosomal location; constitutive androstane receptor; drug induced liver injury; drug metabolism; hepatocyte nuclear factor; histone modification; in vivo Model; novel; outcome prediction; pregnane X receptor; therapy outcome; transcription factor

ABSTRACT The aim of the project is to determine the roles of long non-coding RNAs (lncRNAs) of HNF1a-AS1 and HNF4a-AS1 in the regulation of cytochrome P450 (CYP) gene expression. Drug-metabolizing CYP enzymes are responsible for therapeutic outcomes of 60-70% drugs. Understanding all key factors in the regulation of expression of the CYP enzymes is critical to predict outcomes of drug therapy. Transcription factors (TFs) of hepatocyte nuclear factor 1a (HNF1a), 4a (HNF4a), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) are the key factors. After binding to their response elements, the TFs facilitate transcriptional regulation through alterations of histone modification status of the CYP genes, the major epigenetic mechanism. A remaining question is how the TFs trigger alterations of histone modifications to facilitate the regulation of CYP expression. lncRNAs may be the key components. Increasing evidence has shown that antisense lncRNAs next to TFs on chromosomal locations are involved in the functions of the TFs in regulation of gene expression. We identified two lncRNAs next to the TFs of HNF1a and HNF4a, which are HNF1a-AS1 and HNF4a-AS1. Several fundamental challenge questions need to be addressed. (1) Whether HNF1a-AS1 and HNF4a-AS1 are the two key factors in maintaining homeostasis of P450 enzymes in liver in a dynamic process, such as drug induction, through enhancing by HNF1a-AS1 or repressing by HNF4a-AS1 in the transcriptional regulation of P450 gene expression? (2) Whether HNF1a-AS1 and HNF4a-AS1 are the two key factors in sensitizing susceptibility of drug induced liver injury (DILI) and following process of liver regeneration? (3) How HNF1a-AS1 and HNF4a-AS1 participate in the regulation of P450 gene expression, directly or indirectly through the regulation of PXR or CAR by alteration of histone modifications? These fundamental questions are so critical for deeply understanding molecular mechanisms in the regulation of CYP-mediated drug metabolism and DILI. In the past five years, we have determined the role of lncRNAs in drug metabolism. Our recent progress has placed us into an appropriate position to provide answers to these fundamental questions. We have developed a comprehensive plan to address these challenge questions with both in vitro and in vivo models in the next five years. After completion of the proposed studies, we expect to provide answers to address the challenge questions. The proposed work will elucidate the epigenetic regulatory mechanisms by lncRNAs that control homeostasis of drug- metabolizing CYP expression in a positive and negative feedback loop after exposure to drugs. The proposed work will determine the roles of lncRNAs in P450-mediated drug metabolism and susceptibility to DILI. The generated knowledge will help to identify novel key factors for predicting therapeutic efficacy and DILI.

抽象的 该项目的目的是确定HNF1A-AS1和 在调节细胞色素P450（CYP）基因表达中的HNF4A-AS1。药物代谢CYP 酶负责60-70％药物的治疗结果。了解所有关键因素 CYP酶表达的调节对于预测药物治疗结果至关重要。 肝细胞核因子1A（HNF1A）的转录因子（TF），4A（HNF4A），hindane x受体 （PXR）和组成型雄激素受体（CAR）是关键因素。与他们的反应结合后 元素，TFS通过改变组蛋白修饰状态来促进转录调节 CYP基因，主要的表观遗传机制。剩下的问题是TFS如何触发 组蛋白修饰的改变以促进CYP表达的调节。 lncrnas可能是 关键组件。越来越多的证据表明，染色体上TF旁边的反义LNCRNA 位置参与了TFS在基因表达调节中的功能。我们确定了两个 HNF1A和HNF4A的TFS旁边的LNCRNA，hnf1a-as1和hnf4a-as1。一些 基本挑战问题需要解决。 （1）HNF1A-AS1和HNF4A-AS1是否 在动态过程中维持肝脏中P450酶体内稳态的两个关键因素，例如 药物诱导，通过通过HNF1A-AS1增强或在转录中被HNF4A-AS1抑制 调节P450基因表达？ （2）HNF1A-AS1和HNF4A-AS1是否是两个关键因素 在使药物诱导的肝损伤（DILI）和肝脏再生过程的敏感性中？ （3）HNF1A-AS1和HNF4A-AS1如何直接参与P450基因表达的调节 通过改变组蛋白修饰的改变，通过调节PXR或CAR进行间接？这些 基本问题对于深入了解法规中的分子机制至关重要 CYP介导的药物代谢和DILI。在过去的五年中，我们确定了 药物代谢中的lncRNA。我们最近的进步使我们陷入适当的位置 这些基本问题的答案。我们制定了一个全面的计划来解决这些问题 在未来五年中，在体外和体内模型都挑战问题。完成后 拟议的研究，我们希望提供答案来解决挑战问题。提议 工作将通过LNCRNA阐明表观遗传调节机制，以控制药物的稳态 暴露于药物后，在正反馈循环中代谢CYP表达。这 拟议的工作将确定LNCRNA在P450介导的药物代谢和易感性中的作用 到Dili。生成的知识将有助于确定预测治疗功效的新的关键因素 和Dili。