FV 10i-LIV Conofocal Imaging System (GM094268)

FV 10i-LIV 共焦成像系统 (GM094268)

• 批准号: 9027528
• 负责人: Wei Yue
• 金额: $ 11.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027528
• 关键词: Adenovirus Vector; Adverse effects; Affect; Aging; Antibiotics; Antidiabetic Drugs; Antineoplastic Agents; Bile Acids; Blood; Cardiac Glycosides; Carrier Proteins; Cell Line; Computer Simulation; Data; Digoxin; Disease; Drug Interactions; Drug Kinetics; Drug Transport; Functional disorder; Gene Expression; Genetic Polymorphism; Goals; Green Fluorescent Proteins; Health; Hepatic; Hepatocyte; Human; Immunosuppressive Agents; Lipids; Literature; Liver; Mediating; Membrane; Modeling; Molecular; Mutagenesis; Myopathy; OATP Transporters; Outcome; Pharmaceutical Preparations; Phosphorylation; Plasma; Post-Translational Regulation; Proteasome Inhibition; Proteasome Inhibitor; Protein Kinase C; Proteins; Regulation; Research; Role; Serine; Substrate Interaction; System; Testing; Toxic Environmental Substances; Toxic effect; Toxin; Ubiquitin; Variant; Work; base; clinically relevant; drug candidate; drug development; imaging system; innovation; irinotecan; kinase inhibitor; liver-specific protein; novel; novel strategies; overexpression; prevent; programs; protein function; research study; success; trafficking; uptake

DESCRIPTION (provided by applicant): Hepatic uptake transport proteins are now recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are liver-specific, and are major uptake transport proteins that mediate uptake, from blood into the liver, of a diverse array of endogenous compounds (e.g. bile acids), environmental toxins, and many clinically important drugs, including lipid-lowering statins, antibiotics, immunosuppressants, cardiac glycosides, antidiabetic and anticancer agents. Therefore, OATP proteins have significant relevance to human health. Dysfunction of OATP1B1 and OATP1B3 is closely related with altered drug pharmacokinetics and toxicity. Genetic polymorphisms of OATP1B1 and OATP1B3 that have decreased transport function are associated with markedly increased plasma concentrations/systemic exposure of many substrates (e.g., statins, irinotecan, digoxin). The c. 512T>C (V174A) variant of OATP1B1 is the most robust and important predictor of statin-induced myopathy. The long-term goal of this research program is to define the molecular mechanism(s) that affect drug/toxin disposition through OATP1B1 and OATP1B3, and to predict and prevent OATP-mediated drug-drug interactions in humans. To date, only scattered information is known regarding mechanisms involved in regulating OATP1B1 and OATP1B3 function, most of which were studied at the transcriptional level. The objectives of this application are to elucidate the potential role of posttranslational regulation, via phosphorylation and the ubiquitin system, in modulating OATP1B1 and OATP1B3 function. The proposed studies are based on my preliminary results that: 1) OATP1B3 is a phosphorylated protein and the function of OATP1B1 and OATP1B3 is regulated by protein kinase C activation; 2) the ubiquitin system is involved in OATP1B1 and OATP1B3 degradation, and proteasome inhibition affects OATP1B1 and OATP1B3 function. The specific aims are as follows: Aim 1. Elucidate the impact of altered phosphorylation status on OATP1B1 and OATP1B3 transport function and membrane localization. Aim 2. Define the regulation of OATP1B1 and OATP1B3 degradation and trafficking by the ubiquitin system. The proposed research is innovative and relevant to human health because an understanding of the mechanism(s) that are involved in regulating OATP1B1 and OATP1B3 function is essential to predict potential drug-drug interactions, and provide helpful information in drug development to prevent OATP-mediated drug- drug interactions. The outcomes of these experiments will greatly broaden our ability to predict and prevent transport-mediated drug-drug interactions.

描述（由申请人提供）：肝摄取转运蛋白现在被认为是可变药物反应性和意想不到的药物-药物相互作用的临床相关决定因素。有机阴离子转运多肽 (OATP) 1B1 和 OATP1B3 是肝脏特异性的，是主要的摄取转运蛋白，介导从血液到肝脏的多种内源性化合物（例如胆汁酸）、环境毒素和许多临床上的摄取。重要药物，包括降脂他汀类药物、抗生素、免疫抑制剂、强心苷、抗糖尿病和抗癌药物。因此，OATP蛋白与人类健康具有重要意义。 OATP1B1和OATP1B3的功能障碍与药物药代动力学和毒性的改变密切相关。转运功能降低的 OATP1B1 和 OATP1B3 基因多态性与许多底物（例如他汀类药物、伊立替康、地高辛）的血浆浓度/全身暴露显着增加相关。 c. OATP1B1 的 512T>C (V174A) 变体是他汀类药物引起的肌病最有力、最重要的预测因子。该研究计划的长期目标是确定通过 OATP1B1 和 OATP1B3 影响药物/毒素处置的分子机制，并预测和预防 OATP 介导的人类药物间相互作用。迄今为止，有关调节 OATP1B1 和 OATP1B3 功能的机制仅了解零散的信息，其中大部分是在转录水平上研究的。本申请的目的是阐明翻译后调节通过磷酸化和泛素系统在调节 OATP1B1 和 OATP1B3 功能中的潜在作用。拟议的研究基于我的初步结果：1）OATP1B3是一种磷酸化蛋白，OATP1B1和OATP1B3的功能受蛋白激酶C激活调节； 2）泛素系统参与OATP1B1和OATP1B3降解，蛋白酶体抑制影响OATP1B1和OATP1B3功能。具体目标如下： 目的 1. 阐明磷酸化状态改变对 OATP1B1 和 OATP1B3 转运功能和膜定位的影响。目标 2. 定义泛素系统对 OATP1B1 和 OATP1B3 降解和运输的调节。拟议的研究具有创新性并且与人类健康相关，因为了解参与调节 OATP1B1 和 OATP1B3 功能的机制对于预测潜在的药物间相互作用至关重要，并为药物开发提供有用的信息以防止 OATP 介导的药物-药物相互作用。这些实验的结果将极大地拓宽我们预测和预防转运介导的药物相互作用的能力。

项目成果

Pretreatment With Rifampicin and Tyrosine Kinase Inhibitor Dasatinib Potentiates the Inhibitory Effects Toward OATP1B1- and OATP1B3-Mediated Transport.

• DOI: 10.1016/j.xphs.2017.03.022
• 发表时间: 2017-08
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Pahwa S;Alam K;Crowe A;Farasyn T;Neuhoff S;Hatley O;Ding K;Yue W
• 通讯作者: Yue W

Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models.

• DOI: 10.1016/j.xphs.2020.06.016
• 发表时间: 2021-01
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Kayesh R;Farasyn T;Crowe A;Liu Q;Pahwa S;Alam K;Neuhoff S;Hatley O;Ding K;Yue W
• 通讯作者: Yue W

Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner.

• DOI: 10.1371/journal.pone.0186924
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Alam K;Farasyn T;Crowe A;Ding K;Yue W
• 通讯作者: Yue W

Characterization of Liver- and Cancer-type-Organic Anion Transporting Polypeptide (OATP) 1B3 Messenger RNA Expression in Normal and Cancerous Human Tissues.

• DOI: 10.2174/1872312812666180326110146
• 发表时间: 2018
• 期刊: Drug metabolism letters
• 作者: Alam K;Farasyn T;Ding K;Yue W
• 通讯作者: Yue W

Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins.

• DOI: 10.3390/pharmaceutics16010063
• 发表时间: 2023-12-31
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Powell JT;Kayesh R;Ballesteros-Perez A;Alam K;Niyonshuti P;Soderblom EJ;Ding K;Xu C;Yue W
• 通讯作者: Yue W