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Pharmacogenomics and Mechanisms of Cytidine Analogues

胞苷类似物的药物基因组学和机制

基本信息

批准号：
8433231
负责人：
Liewei Wang
金额：
$ 28.59万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433231
关键词：
AKT inhibition Affect Amino Acid Sequence Animal Model Apoptotic Biological Markers Biological Models Breast Breast Cancer Cell Cancer Patient Candidate Disease Gene Cells Clinical Correlation Studies Cytidine DNA DNA Resequencing DNA Sequence Data Drug Targeting Enzymes Exons Future Gene Expression Gene Proteins Genes Genetic Polymorphism Genetic Variation Genotype Health Human Immunophilins Inhibitory Concentration 50 Introns Knowledge Malignant neoplasm of pancreas Mediator of activation protein Metabolism Non-Small-Cell Lung Carcinoma Nucleic Acid Regulatory Sequences Nude Mice Ovarian Pancreas Pathway interactions Patients Pharmaceutical Preparations Pharmacogenomics Phenotype Phosphoric Monoester Hydrolases Phosphorylation Play Process Proto-Oncogene Proteins c-akt RNA RNA Splicing Research Resistance Role Sampling Series Signal Transduction Single Nucleotide Polymorphism Testing Tissue Sample Tissues Tumor Cell Line Tumor Tissue Variant analog base chemotherapy cytotoxicity drug metabolism follow-up functional genomics gemcitabine genome-wide in vivo insight lymphoblastoid cell line mouse model novel protein function protein protein interaction research study response screening tumor

项目摘要

DESCRIPTION (provided by applicant): The cytidine analogue gemcitabine is first line chemotherapy for the treatment of pancreatic cancer, and it has also shown promising results in the treatment of breast cancer and non-small cell lung cancer. Gemcitabine has its effect as a result of a "pathway" that includes drug transporters, enzymes catalyzing drug activation and inactivation, and drug targets. However, very little is known with regard to determinants of variation in gemcitabine response, especially single nucleotide polymorphisms (SNPs) in genes outside of the pathway described by our current knowledge of this drug. In order to identify additional genes of importance for variation in gemcitabine response, we have used 300 Human Variation Panel lymphoblastoid cell line as a model system for common genetic variation to perform genome-wide expression association studies to identify genes with expression levels that were significantly associated with variation in gemcitabine cytotoxicity (IC50 values). One top candidate gene, FKBP5, a gene encoding a 51 kDa immunophilin, was shown to affect the apoptotic pathway in response to gemcitabine. Specifically, lower expression of FKBP5 was associated with resistance to gemcitabine-induced cytotoxicity. We also demonstrated an inhibitory role for FKBP5 in AKT phosphorylation. As a result, we hypothesize that FKBP5 affects gemcitabine response by negatively regulating AKT activation and that genetic variation associated with FKBP5 gene expression and protein function might contribute significantly to variation in gemcitabine response. In this application, we propose to determine mechanisms by which FKBP5 regulates AKT activation, followed by testing the role of FKBP5 in gemcitabine response using mice models and tumor samples from pancreatic cancer patients treated with gemcitabine. In addition, we will also determine gene sequence variation that is associated with FKBP5 gene expression and response to gemcitabine using 300 lymphoblastoid cell lines, followed by performing functional genomic studies with these SNPs. Finally, we will perform a genotype-phenotype correlation study with DNA from pancreatic cancer patients to determine whether SNPs that affect FKBP5 expression and/or protein function might influence response to gemcitabine when used to treat pancreatic cancer. In summary, this comprehensive series of experiments will enhance our understanding of mechanisms of gemcitabine resistance and may identify biomarkers that might help predict gemcitabine response in the treatment of pancreatic cancer.

描述（由申请人提供）：胞苷类似物吉西他滨是治疗胰腺癌的一线化疗药物，在治疗乳腺癌和非小细胞肺癌方面也显示出良好的效果。吉西他滨的作用是由于药物转运体、催化药物活化和失活的酶和药物靶标的“途径”。然而，关于吉西他滨反应变异的决定因素，特别是我们目前对这种药物的知识所描述的途径之外的基因中的单核苷酸多态性（snp），我们知之甚少。为了确定吉西他滨反应变异的其他重要基因，我们使用300个人类变异小组淋巴母细胞系作为常见遗传变异的模型系统，进行全基因组表达关联研究，以确定表达水平与吉西他滨细胞毒性变异（IC50值）显著相关的基因。其中一个最重要的候选基因FKBP5编码一个51 kDa的亲免疫蛋白，被证明在对吉西他滨的反应中影响凋亡途径。具体来说，FKBP5的低表达与对吉西他滨诱导的细胞毒性的耐药性有关。我们还证明了FKBP5在AKT磷酸化中的抑制作用。因此，我们假设FKBP5通过负调控AKT激活影响吉西他滨应答，与FKBP5基因表达和蛋白功能相关的遗传变异可能是吉西他滨应答变化的重要原因。在本研究中，我们拟确定FKBP5调控AKT激活的机制，然后利用小鼠模型和接受吉西他滨治疗的胰腺癌患者的肿瘤样本检测FKBP5在吉西他滨应答中的作用。此外，我们还将利用300种淋巴母细胞样细胞系确定与FKBP5基因表达和对吉西他滨反应相关的基因序列变异，随后对这些snp进行功能基因组研究。最后，我们将对胰腺癌患者的DNA进行基因型-表型相关性研究，以确定影响FKBP5表达和/或蛋白质功能的snp是否会影响用于治疗胰腺癌的吉西他滨的反应。总之，这一系列全面的实验将增强我们对吉西他滨耐药机制的理解，并可能识别出可能有助于预测吉西他滨治疗胰腺癌反应的生物标志物。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

No Association Between Antidepressant Efficacy and rs28365143 in Corticotropin-Releasing Hormone Binding Protein in a Large Meta-Analysis.

大型荟萃分析表明，抗抑郁功效与促肾上腺皮质激素释放激素结合蛋白的 rs28365143 之间没有关联。

DOI：
10.1176/appi.ajp.2018.18010070
发表时间：
2018
期刊：
The American journal of psychiatry
影响因子：
0
作者：
Fabbri,Chiara;Lewis,CathrynM;Perlis,RoyH;Uher,Rudolf
通讯作者：
Uher,Rudolf

Computational discovery of transcription factors associated with drug response.

DOI：
10.1038/tpj.2015.74
发表时间：
2016-11
期刊：
The pharmacogenomics journal
影响因子：
0
作者：
Hanson C;Cairns J;Wang L;Sinha S
通讯作者：
Sinha S

In vitro human cell line models to predict clinical response to anticancer drugs.

DOI：
10.2217/pgs.14.170
发表时间：
2015
期刊：
Pharmacogenomics
影响因子：
2.1
作者：
Niu N;Wang L
通讯作者：
Wang L

Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system.

DOI：
10.3389/fgene.2013.00166
发表时间：
2013
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Jiang J;Fridley BL;Feng Q;Abo RP;Brisbin A;Batzler A;Jenkins G;Long PA;Wang L
通讯作者：
Wang L

Principled multi-omic analysis reveals gene regulatory mechanisms of phenotype variation.