MRP4 in Drug Sensitivity and Physiology

MRP4 在药物敏感性和生理学中的应用

基本信息

批准号：
8308677
负责人：
JOHN D SCHUETZ
金额：
$ 51.2万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308677
关键词：
6-Mercaptopurine ATP-Binding Cassette Transporters Abbreviations Accounting Acute Adult Adverse effects Affect Aging Anabolism Androgens Animal Model Animals Antibodies Arachidonic Acids Bile Acids Binding Biological Models Biological Process Biology Blood - brain barrier anatomy Brain CCL21 gene Cell Maturation Cell physiology Cholestasis Data Defect Development Disease Electron Microscopy Enzymes Evolution Feedback Food Funding Gametogenesis Ganciclovir Gene Expression Genes Genetic Models Germ Cells Goals Gynecomastia Health Hepatic Homeostasis Hormones Human Hydroxysteroid Dehydrogenases Imatinib Immunoassay Integrin alpha6 Knock-out Knockout Mice Knowledge Laboratory Study Lead Left Link Metabolism Microarray Analysis Mixed Function Oxygenases Modeling Molecular Mus P-Glycoproteins PDGFRB gene PTGS2 gene Pathway interactions Pattern Pharmaceutical Preparations Physiological Physiology Platelet-Derived Growth Factor Receptor Play Population Predisposition Process Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Puberty Recovery Regulation Role Seminiferous tubule structure Series Serum Side Source Stem cells System Testing Testis Testosterone Therapeutic Toxic effect Up-Regulation Variant Work Xenobiotics abstracting arachidonate base chemotherapeutic agent cytotoxic drug sensitivity fatty acid-binding proteins human FABP4 protein in vivo in vivo Model insight leydig interstitial cell male novel polyphenol prevent prostaglandin transporter reproductive solute testosterone biosynthesis thiopurine

项目摘要

Abstract Studies over the last funding period were directed to elucidating the function and molecular regulation of the ABC transporter, Mrp4. The current proposal represents an evolution of this work, based upon recent studies from this laboratory using the Mrp4-/- mouse we developed, and using our anti-Mrp4 antibodies, we determined that Mrp4 is highly expressed in both human and murine Leydig cells in the testes. As the Leydig cells are responsible for supplying systemic testosterone we evaluated the Mrp4-/- mice for serum levels of testosterone despite the fact that testosterone is not a substrate for Mrp4. We found that as Mrp4 gene copy decreases there are corresponding reductions in serum testosterone that are directly associated with reduced expression of Mrp4 in Leydig cells. We hypothesized that elevated prostaglandins (PG) (a known Mrp4 substrate) might be responsible for this effect because PG inhibit testosterone synthesis. The enzyme responsible for formation of PG, COX-2 is expressed in Leydig cells and COX-2 inhibition increases systemic testosterone levels. In adult Mrp4-/- mice the level of testosterone is restored and PG levels are reduce in the Mrp4-/-. These findings led us to hypothesize that, in the testes, compensatory pathways re-activated testosterone synthesis in the absence of Mrp4. Our preliminary data shows, in testes, upregulation of genes directly linked to PG metabolism (although COX-2 is unchanged, however one gene encoding a protein known to bind PG (FABP4) is upregulated). These findings in this model system are of human relevance because chemotherapeutic agents (e.g., imatinib, ganciclovir) and food components (polyphenols) that inhibit Mrp4 cause acute reduction in testosterone and reproductive effects. We hypothesize they produce these effects by interfering with Mrp4 transport. Our in vivo model will allow us to directly test how they impair testosterone biosynthesis. These findings raise the intriguing possibility that, in the absence of Mrp4, alternate pathways can be activated in Leydig cells to restore testosterone biosynthesis. The objectives of the proposed studies are to: i) to elucidate how post-puberty Mrp4-/- mice achieve normal testosterone levels; ii) determine if Mrp4-/- vs Mrp4 +/+ have altered differentiation status; iii) evaluate the role of fatty-acid binding protein 4 (FABP4), a protein known to bind PG, in regulating testosterone biosynthesis in model systems; iv) determine if chemotherapeutic agents and xenobiotics known to alter testosterone levels do so by interfereing with Mrp4 function. The proposed studes are supported by preliminary data from the Mrp4-/- and Mrp4+/+ mice and are of direct human relevance.

抽象的在上一个资金期间的研究是针对阐明功能和 ABC转运蛋白的分子调节MRP4。当前的提议代表这项工作的演变是根据该实验室的最新研究使用MRP4 - / - 我们开发的鼠标，并使用抗MRP4抗体，我们确定MRP4为在睾丸中的人类和鼠Leydig细胞中高度表达。作为莱迪格细胞负责提供全身睾丸激素，我们评估了MRP4 - / - 小鼠对于血清睾丸激素水平，尽管睾丸激素不是底物 MRP4。我们发现，随着MRP4基因拷贝的减少，有相应的减少在血清睾丸激素中与MRP4表达直接相关的血清睾丸激素中 leydig细胞。我们假设升高前列腺素（PG）（已知的MRP4 底物）可能是由于PG抑制睾丸激素的合成而导致的。负责PG形成Cox-2的酶在Leydig细胞和 COX-2抑制增加了全身睾丸激素水平。在成年MRP4 - / - 小鼠中恢复睾丸激素，MRP4 - / - 降低PG水平。这些发现导致我们假设在睾丸中，代偿途径重新激活睾丸激素在没有MRP4的情况下合成。我们的初步数据在睾丸中显示了与PG代谢直接相关的基因（尽管COX-2没有变化，但是一个编码已知结合Pg（FabP4）的蛋白质的基因被上调。这些发现该模型系统具有人类相关性，因为化学治疗剂（例如，伊马替尼，ganciclovir）和食品成分（多酚）抑制MRP4引起急性睾丸激素和生殖作用的降低。我们假设它们产生这些通过干扰MRP4运输的影响。我们的体内模型将使我们能够直接测试它们如何损害睾丸激素的生物合成。这些发现提出了有趣的可能性在没有MRP4的情况下，可以在Leydig细胞中激活替代途径恢复睾丸激素生物合成。拟议研究的目标是：i）阐明puberty后MRP4 - / - 小鼠如何达到正常的睾丸激素水平； ii）确定MRP4 - / - vs MRP4 +/ +是否有改变的分化状态； iii）评估脂肪酸结合蛋白4（FabP4），一种已知结合Pg的蛋白，在调节中模型系统中的睾丸激素生物合成； iv）确定化学治疗剂是否已知会改变睾丸激素水平的异生元通过干扰MRP4来做到这一点功能。提出的研究由MRP4 - / - 和 MRP4+/+小鼠具有直接的人类相关性。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Leukemia and ABC transporters.

DOI：
10.1016/bs.acr.2014.10.006
发表时间：
2015
期刊：
ADVANCES IN CANCER RESEARCH
影响因子：
0
作者：
Fukuda, Yu;Lian, Shangli;Schuetz, John D.
通讯作者：
Schuetz, John D.

Impaired 2',3'-dideoxy-3'-thiacytidine accumulation in T-lymphoblastoid cells as a mechanism of acquired resistance independent of multidrug resistant protein 4 with a possible role for ATP-binding cassette C11.

T 淋巴母细胞中 2,3-二脱氧-3-硫胞苷积累受损，作为获得性耐药机制，独立于多药耐药蛋白 4，可能与 ATP 结合盒 C11 发挥作用。

DOI：
10.1042/bj20020494
发表时间：
2002
期刊：
The Biochemical journal
影响因子：
0
作者：
Turriziani,O;Schuetz,JD;Focher,F;Scagnolari,C;Sampath,J;Adachi,M;Bambacioni,F;Riva,E;Antonelli,G
通讯作者：
Antonelli,G

The effects of prolonged treatment with zidovudine, lamivudine, and abacavir on a T-lymphoblastoid cell line.

齐多夫定、拉米夫定和阿巴卡韦长期治疗对 T 淋巴细胞系的影响。

DOI：
10.1089/aid.2006.22.960
发表时间：
2006
期刊：
AIDS research and human retroviruses
影响因子：
1.5
作者：
Turriziani,Ombretta;Pagnotti,Paolo;Pierangeli,Alessandra;Focher,Federico;Baranello,Cinzia;Bellomi,Francesca;Falasca,Francesca;Morgan,Jessica;Schuetz,JohnD;Antonelli,Guido
通讯作者：
Antonelli,Guido

The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6.

DOI：
10.1038/ncomms12353
发表时间：
2016-08-10
期刊：
Nature communications
影响因子：
16.6
作者：
Fukuda Y;Cheong PL;Lynch J;Brighton C;Frase S;Kargas V;Rampersaud E;Wang Y;Sankaran VG;Yu B;Ney PA;Weiss MJ;Vogel P;Bond PJ;Ford RC;Trent RJ;Schuetz JD
通讯作者：
Schuetz JD

Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

DOI：
10.1124/mol.62.6.1321
发表时间：
2002-12
期刊：
Molecular pharmacology
影响因子：
3.6
作者：
P. Wielinga;G. Reid;E. E. Challa-E.;I. V. D. Heijden;L. V. Deemter;M. Haas;C. Mol;A. Kuil;E. Groeneveld;J. Schuetz;C. Brouwer;R. D. Abreu;J. Wijnholds;J. Beijnen;P. Borst
通讯作者：
P. Wielinga;G. Reid;E. E. Challa-E.;I. V. D. Heijden;L. V. Deemter;M. Haas;C. Mol;A. Kuil;E. Groeneveld;J. Schuetz;C. Brouwer;R. D. Abreu;J. Wijnholds;J. Beijnen;P. Borst