Pharmacogenomic regulation of CYP transcription by TSPYL genes

TSPYL 基因对 CYP 转录的药物基因组调控

• 批准号: 10062988
• 负责人: Liewei Wang
• 金额: $ 30.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062988
• 关键词: Affect; CYP2C19 gene; CYP2C9 gene; CYP3A4 gene; Cause of Death; Cessation of life; Clinical; Clinical Treatment; Copy Number Polymorphism; Cytochrome P450; DNA Sequence Alteration; Data; Drug Kinetics; Drug Labeling; Drug Regulations; Enzymes; Family; Family member; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; HNF4A gene; Hospitals; In Vitro; Knowledge; Metabolism; MicroRNAs; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacotherapy; Phase; Phenotype; Plasma; Protein Family; Proteins; Regulation; Testing; Therapeutic; Toxic effect; Transcriptional Regulation; Treatment outcome; United States; Variant; abiraterone; adverse drug reaction; drug efficacy; drug metabolism; epigenetic regulation; gene expression variation; gene function; genetic variant; inter-individual variation; interest; liver metabolism; novel; pharmacokinetics and pharmacodynamics; phase 1 study; protein function; response; side effect; transcription factor; virtual

Variation in drug response could affect both the efficacy and toxicity of virtually all drugs. Adverse drug reactions are the 4th leading cause of death in the United States. Therefore, to understand factors that might contribute to this variation and to use that information to help maximize drug efficacy and to minimize side effects would represent a major advance. Host genetics, among many factors, contributes significantly to variation in drug response. Genetic variation within genes encoding proteins determining drug concentrations, so called pharmacokinetic pathways, and proteins determining the effect of the drug, so called pharmacodynamics, can both influence drug response. The well-studied Phase I metabolism enzymes, the cytochromes P450 (CYPs), are highly genetically polymorphic. Many CYP genes contain variants with known clinical utility and have been incorporated into FDA drug labeling or relabeling. Among the CYP family genes, CYP3A4, CYP2C9 and CYP2C19, taken together, metabolize more than 50% of all drugs. The regulation of these genes is of great interest and importance from both basic scientific and clinical points of view. Even though SNPs and copy number variation (CNV) that cis-regulate CYP gene function have been well-studied, they do not explain all of the inter-individual variability in the function of these genes. Previous evidence indicates the functional significance of the trans-regulation of CYPs through genetic variation in transcription factors, microRNAs or epigenetic regulation. These findings serve to emphasize the crucial need to identify mechanisms underlying the transcriptional regulation of CYP genes and to identify genomic alterations responsible for variation in these regulatory mechanisms which, in turn, contribute to variation in CYP gene function and—ultimately--drug response. As a result, enhancing our basic knowledge of the transcription of CYPs would help to us build more comprehensive regulatory networks for CYP gene expression and function, and this knowledge would enhance our ability to individualize drug therapy. In this application, our extensive preliminary data have shown that a novel family of proteins, the TSPYL family, can function as transcription factors, contributing significantly to regulation of the expression of CYP2C and 3A family members. Our Preliminary Data showed that a functional SNP in TSPYL1 can influence in vitro level and clinical response of abiraterone, a drug that is metabolized by CYP 3A4. Here, we propose to study mechanisms by which TSPYL family members might regulate CYP gene expression as well as the contribution of genetic variation that either cis or trans-regulates TSPYL genes to inter-individual variation in CYP gene expression and in drug response phenotypes. We believe that our novel finding could add another comprehensive layer to our understanding of the transcription regulation of CYPs, which could, in turn, contribute significantly to understanding of variation in drug response.

药物反应的变化可以影响几乎所有药物的疗效和毒性。药物不良 反应是美国第四大死亡原因。因此，为了了解 可能有助于这种变化，并利用这些信息来帮助最大限度地提高药物疗效， 最大限度地减少副作用将是一个重大进步。在许多因素中，宿主遗传学 对药物反应的变化有显著影响。编码决定药物的蛋白质的基因内的遗传变异 浓度，所谓的药代动力学途径，和蛋白质决定药物的作用，所谓的 药效学，都可以影响药物反应。研究充分的I相代谢酶， 细胞色素P450（CYP）是高度遗传多态性的。许多抗肿瘤基因含有已知的 临床实用性，并已纳入FDA药物标签或重新标签。在这些家族基因中， CYP3A4、CYP2C9和CYP2C19加在一起代谢了所有药物的50%以上。调控 从基础科学和临床的角度来看，这些基因的研究都是非常有趣和重要的。 尽管顺式调节β基因功能的SNP和拷贝数变异（CNV）已经被发现， 尽管研究得很好，但它们并不能解释这些基因功能的所有个体间变异。 先前的证据表明，CYP通过遗传调节的反式调节的功能意义。 转录因子、microRNA或表观遗传调控的变异。这些发现强调了 迫切需要确定潜在的转录调控机制的基因，并确定 基因组改变导致这些调节机制的变化，反过来又有助于 基因功能的变异以及最终的药物反应。因此，提高我们的基本知识 CYPs转录的研究将有助于我们建立更全面的CYPs调控网络 基因表达和功能，这些知识将提高我们的能力，个性化药物 疗法在本申请中，我们广泛的初步数据表明，一个新的蛋白质家族， TSPYL家族，可以作为转录因子发挥作用，显著促进调节TSPYL的表达。 CYP2C和3A家族成员。我们的初步数据表明，TSPYL1中的功能性SNP可以影响 阿比特龙的体外水平和临床反应，阿比特龙是一种由β 3A4代谢的药物。在此，我们建议 研究TSPYL家族成员可能调节TSPYL基因表达的机制， 顺式或反式调节TSPYL基因的遗传变异对个体间 基因表达和药物反应表型的变化。我们相信我们的新发现 可以为我们对CYP转录调控的理解增加另一个全面的层面， 反过来，可以大大有助于了解药物反应的变化。

项目成果

Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.

• DOI: 10.1158/1541-7786.mcr-22-0099
• 发表时间: 2022-12-02
• 期刊: MOLECULAR CANCER RESEARCH
• 影响因子: 5.2
• 作者: Sicotte, Hugues;Kalari, Krishna R.;Qin, Sisi;Dehm, Scott M.;Bhargava, Vipul;Gormley, Michael;Tan, Winston;Sinnwell, Jason P.;Hillman, David W.;Li, Ying;Vedell, Peter T.;Carlson, Rachel E.;Bryce, Alan H.;Jimenez, Raphael E.;Weinshilboum, Richard M.;Kohli, Manish;Wang, Liewei
• 通讯作者: Wang, Liewei

SLCO1B1: Application and Limitations of Deep Mutational Scanning for Genomic Missense Variant Function.

SLCO1B1：对基因组错义变异功能的深突变扫描的应用和局限性。

• DOI: 10.1124/dmd.120.000264
• 发表时间: 2021-05
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Zhang L;Sarangi V;Ho MF;Moon I;Kalari KR;Wang L;Weinshilboum RM
• 通讯作者: Weinshilboum RM

Pharmacogenomics in Practice.

药物基因组学实践。

• DOI: 10.1002/cpt.1600
• 发表时间: 2019
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Wang,Liewei;Weinshilboum,Richard
• 通讯作者: Weinshilboum,Richard

Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer.

• DOI: 10.1002/cpt.2582
• 发表时间: 2022-06
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7

Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo.

CHK1 抑制对 CPX-351 体外和离体细胞毒性的影响。

• DOI: 10.1038/s41598-019-40218-0
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Vincelette,NicoleD;Ding,Husheng;Huehls,AmeliaM;Flatten,KarenS;Kelly,RebeccaL;Kohorst,MiraA;Webster,Jonathan;Hess,AllanD;Pratz,KeithW;Karnitz,LarryM;Kaufmann,ScottH
• 通讯作者: Kaufmann,ScottH