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: 10557132
• 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/10557132
• 关键词: Address; Binding; Cytochrome P450; Enzymes; Epigenetic Process; Exposure to; Feedback; Gene Expression; Gene Expression Regulation; Genes; HNF4A gene; Homeostasis; In Vitro; Knowledge; Liver; Liver Regeneration; Mediating; Molecular; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predictive Factor; Predisposition; Process; Regulation; Repression; 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 的长非编码 RNA (lncRNA) 和 HNF4a-AS1 参与细胞色素 P450 (CYP) 基因表达的调节。药物代谢CYP 60-70% 药物的治疗效果是由酶决定的。了解所有关键因素 CYP 酶表达的调节对于预测药物治疗的结果至关重要。 肝细胞核因子 1a (HNF1a)、4a (HNF4a)、孕烷 X 受体的转录因子 (TF) （PXR）和组成型雄甾烷受体（CAR）是关键因素。绑定他们的回应后 元件，转录因子通过组蛋白修饰状态的改变促进转录调控 CYP 基因，主要的表观遗传机制。剩下的问题是 TF 如何触发 改变组蛋白修饰以促进 CYP 表达的调节。 lncRNA 可能是 关键部件。越来越多的证据表明，染色体上紧邻 TF 的反义 lncRNA 位置参与转录因子在基因表达调节中的功能。我们确定了两个 HNF1a和HNF4a的TF旁边的lncRNA，即HNF1a-AS1和HNF4a-AS1。一些 需要解决基本的挑战问题。 (1)HNF1a-AS1和HNF4a-AS1是否为 在动态过程中维持肝脏P450酶稳态的两个关键因素，例如 药物诱导，通过 HNF1a-AS1 的增强或 HNF4a-AS1 的转录抑制 P450基因表达的调控？ (2)HNF1a-AS1和HNF4a-AS1是否是两个关键因素 药物性肝损伤（DILI）的敏感性和肝再生过程中的作用？ (3) HNF1a-AS1和HNF4a-AS1如何直接或间接参与P450基因表达的调控 通过改变组蛋白修饰间接调节 PXR 或 CAR？这些 基本问题对于深入理解调控的分子机制至关重要 CYP 介导的药物代谢和 DILI 的研究。过去五年，我们确定了自己的角色 药物代谢中的lncRNA。我们最近的进展使我们处于适当的位置，可以提供 这些基本问题的答案。我们制定了一项全面的计划来解决这些问题 在未来五年内通过体外和体内模型挑战问题。完成后 拟议的研究，我们期望提供解决挑战问题的答案。拟议的 这项工作将阐明控制药物稳态的lncRNA的表观遗传调控机制 暴露于药物后以正反馈循环和负反馈循环代谢 CYP 表达。这 拟议的工作将确定 lncRNA 在 P450 介导的药物代谢和敏感性中的作用 到帝力。生成的知识将有助于确定预测治疗效果的新关键因素 和帝力。