A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition

一种新型 lncRNA 响应性和异生素受体介导的药物代谢和处置调节

基本信息

批准号：
10096096
负责人：
Da Yang
金额：
$ 35.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10096096
关键词：
Affect Bioinformatics Biological Assay Biological Process Breast Cancer Cell Cancer Cell Growth Regulation Cancer Patient Cancer cell line Cell physiology ChIP-seq Chemoresistance Chemotherapy-Oncologic Procedure Clinical Clinical Management Code Computer Analysis Data Databases Development Dimensions Doxorubicin Drug Efflux Drug Interactions Drug Regulations Drug Screening Enzymes Evolution Excretory function Genes Genetic Transcription Genomics Genotype Goals Immunoprecipitation In Vitro Length Location Luciferases Machine Learning Malignant Neoplasms Mediating Medical Metabolism Modeling Molecular Cloning Nuclear Receptors Nucleotides Outcome Pharmaceutical Preparations Pharmacogenomics Primary Neoplasm Prognosis Proteins RNA RNA analysis RNA-Protein Interaction Regulation Reporter Genes Research Resistance Resistance development Sampling Specificity Technology Testing Tissues Transcriptional Regulation Transfection Treatment Efficacy Untranslated RNA Up-Regulation Validation Xenobiotics absorption base cancer cell cancer therapy cancer type chemotherapy constitutive androstane receptor crosslinking and immunoprecipitation sequencing docetaxel drug candidate drug disposition drug metabolism gain of function in vivo knock-down novel novel strategies overexpression pharmacokinetics and pharmacodynamics pregnane X receptor receptor response transcriptome sequencing tumor uptake

项目摘要

A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition Abstract Drug metabolism and disposition are essential xenobiotic responses. The long non-coding RNAs (lncRNAs) are non-coding RNAs larger than 200 nucleotides (nt) in length and do not have protein-coding potentials. Although many of the biological functions of lncRNAs have been recognized, it is unclear whether and how lncRNAs can regulate the expression of drug-metabolizing enzymes and transporters and if so, whether the regulations are implicated in cancer chemo-resistance. Through integrative analysis of cancer non-coding genomic and high-through drug screening data of 505 cancer cell lines, our preliminary study have discovered and functionally characterized a group of ADME(drug absorption, distribution, metabolism, and excretion) chemo-resistance lncRNAs, including LINC00992, whose up-regulation is associated with resistance to more than 100 chemotherapy compounds and may regulate drug-metabolizing enzymes and transporters through interacting with xenobiotic nuclear receptor. We hypothesize that dysregulation of ADME chemo-resistance lncRNAs is an important contributor for the development of cancer chemo-resistance. Mechanistically, ADME chemo-resistance lncRNAs affect chemo-resistance through their regulation of drug-metabolizing enzymes and transporters that are responsible for the metabolism and disposition of chemotherapy drugs. We propose three specific aims to test our hypotheses: In Aim 1, we will perform bioinformatic analysis and molecularly clone of lncRNAs associated with cancer chemo-resistance and clinical prognosis. In Aim 2: we will functional characterize of ADME chemo-resistance lncRNAs, including LINC00992, using in vivo and in vitro cancer chemotherapy models. In Aim 3: we will determine the mechanism by which ADME chemo-resistance lncRNAs, including LINC00992, regulate the expression of drug-metabolizing enzymes and transporters. Chemotherapy remains a mainstay in the clinical management of cancer patients, but chemo-resistance is a major challenge to overcome. Understanding the novel lncRNA responsive and xenobiotic nuclear receptor- mediated chemo-resistance will help provide novel strategies to enhance therapeutic efficacy and avoid the development of chemo-resistance.

一种新的lncRNA响应性和异生素受体介导的药物代谢调节性格抽象的药物代谢和处置是重要的外源性反应。长链非编码 RNA (lncRNA) 是长度超过 200 个核苷酸 (nt) 的非编码 RNA，不具有蛋白质编码潜力。尽管lncRNA的许多生物学功能已被认识，但尚不清楚是否以及如何 lncRNA可以调节药物代谢酶和转运蛋白的表达，如果是的话，是否法规与癌症化疗耐药性有关。通过癌症非编码的综合分析 505个癌细胞系的基因组和高通量药物筛选数据，我们的初步研究发现并对一组ADME（药物吸收、分布、代谢和排泄）进行功能表征化疗耐药性 lncRNA，包括 LINC00992，其上调与更多耐药性相关超过 100 种化疗化合物，并可通过调节药物代谢酶和转运蛋白与异生核受体相互作用。我们假设 ADME 化疗耐药性失调 lncRNA 是癌症化疗耐药性发展的重要贡献者。从机制上讲，ADME 化疗耐药性 lncRNA 通过调节药物代谢酶和酶来影响化疗耐药性负责化疗药物的代谢和处置的转运蛋白。我们提出三个具体目标是检验我们的假设：在目标 1 中，我们将进行生物信息学分析和分子克隆 lncRNA与癌症化疗耐药和临床预后相关。目标 2：我们将发挥作用使用体内和体外癌症表征 ADME 化疗耐药性 lncRNA（包括 LINC00992）化疗模型。目标 3：我们将确定 ADME 化学抗性的机制 lncRNA，包括 LINC00992，调节药物代谢酶和转运蛋白的表达。化疗仍然是癌症患者临床治疗的支柱，但化疗耐药性是一个问题需要克服的重大挑战。了解新型 lncRNA 反应性和异生核受体 - 介导的化疗耐药性将有助于提供新的策略来增强治疗效果并避免化学抗性的发展。