DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) DEFICIENCY IN POPULATION STUDIES

人群研究中的二氢嘧啶脱氢酶 (DPD) 缺陷

• 批准号: 7603180
• 负责人: ROBERT B. DIASIO
• 金额: $ 0.72万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603180
• 关键词: 3' Untranslated Regions; Affect; Binding; Biochemical; Blood; Cancer Patient; Catabolism; Collection; Computer Retrieval of Information on Scientific Projects Database; DPYD gene; Data; Defect; Diagnostic tests; Dihydropyrimidinase; Dihydropyrimidine Dehydrogenase; Drug Kinetics; Elements; Enzymes; Fibroblasts; Fluorouracil; Funding; Future; Gene Expression; Genes; Genetic; Goals; Grant; Half-Life; Hour; Institution; Introns; Laboratories; Life; Link; Messenger RNA; Molecular; Mutation Analysis; Nucleic Acid Regulatory Sequences; Nurses; Orotate Phosphoribosyltransferase; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phosphorylase Kinase; Plasma; Population Study; Predisposition; Proteins; Pyrimidine; Pyrimidines; Regulation; Regulator Genes; Regulatory Element; Reporting; Research; Research Personnel; Research Project Grants; Resources; Role; Secondary to; Site; Source; Syndrome; System; Testing; Thymidine Phosphorylase; Thymidylate Synthase; Toxic effect; Translating; Ubiquitin; United States National Institutes of Health; Uridine; base; beta-ureidopropionate; enzyme activity; fluoropyrimidine; improved; multicatalytic endopeptidase complex; mutant; promoter; transcription factor; user-friendly

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Deficiencies in dihydropyrimidine dehydrogenase (DPD) and other enzymes of the pyrimidine catabolic pathway is critical in the predisposition to severe, unanticipated 5-fluorouracil (5-FU) toxicity. Rationale: We, and others, have linked molecular defects in the DPYD gene (the gene that encodes the DPD enzyme) to reduced enzyme activity. This decreased enzyme activity has been shown by our laboratory and others to result in decreased 5-FU clearance and increased 5-FU exposure. Other investigators have reported similar observations with the other enzymes of the pyrimidine catabolic pathway. Specifically, life-threatening 5-FU toxicities have been observed in cancer patients with dihydropyrimidinase (DPYS) and beta-ureidopropionate (BUP) deficiencies. Study Objectives: The long-term objective of this research project is to better understand the genetic basis for severe, potentially life-threatening toxicity secondary to treatment with 5-Fluorouracil (5-FU). To accomplish this goal, we will a) continue to further characterize the pharmacogenetic syndrome of DPD deficiency and b) characterize DPYD and BUP deficiencies. To accomplish these goals we will continue to obtain and utilize biochemical and molecular data (e.g., enzyme activity, mRNA levels, and analysis for mutations in pyrimidine catabolic genes) from patients presenting with grade IV toxicity after 5-FU therapy. In particular, we will examine: 1) the role of additional transcriptional regulatory elements affecting DPYD gene expression including identification of a) transcription factor(s) that bind to regulatory elements I and II in the previously identified promoter, and b) additional potential regulatory regions in introns 1 and the 3'-untranslated region; 2)-Determine the role of the ubiquitin (Ub)-proteasome system in the regulation of DPD protein- a) determine DPD protein half-life for wild type and mutant DPD protein, and b) identify putative destabilizing element(s) of DPD protein; 3) Develop user-friendly diagnostic tests for DPD deficiency and other deficiencies of the pyrimidine catabolic pathway including a) phenotypic tests and b) genotypic tests; 4) the role of other factors which may contribute to severe 5-FU toxicity including a} altered gene expression of the 5-FU site of action - thymidylate synthase, b) altered gene expression of anabolic enzymes, e.g. uridine and thymidine phosphorylases and kinases and orotate phosphoribosyltransferase, and c) altered gene expression of other catabolic enzymes, e.g. dihydropyrimidinase and BUP. Utilization of GCRC Resources: The nursing and laboratory staff has been utilized to 1) perform blood collection from 5-FU toxic cancer patients (over 350 to date) 2) perform pharmacokinetic studies which examine pyrimidine catabolism in 5-FU toxic cancer patients (8 hours per patient; over 25 patients to date) 3) isolation of plasma by laboratory staff from 5-FU toxic cancer patients who have performed the pharmacokinetic study, 4) culturing and maintainence of fibroblasts from 5-FU toxic, DPD deficient, DPYS deficiency, and BUP deficient subjects/cancer patients. Study Population and Outcome: Successful progress on this research project should translate into improved care for patients receiving fluoropyrimidine drugs in the future.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景：嘧啶分解代谢途径的二氢嘧啶脱氢酶（DPD）和其他酶的缺陷对于严重，意外的5-氟尿嘧啶（5-FU）毒性的倾向至关重要。 基本原理：我们和其他人在DPYD基因（编码DPD酶的基因）中已将分子缺陷联系起来，以降低酶活性。 我们的实验室和其他酶活性降低，导致5-FU清除率下降并增加5-FU的暴露。 其他研究人员报告了与嘧啶分解代谢途径的其他酶相似的观察结果。具体而言，在二氢吡啶酶（DPYS）和β-纤维蛋白丙酸酯（BUP）缺乏症的癌症患者中已经观察到了威胁生命的5-FU毒性。研究目标：该研究项目的长期目标是更好地理解以5-氟尿嘧啶（5-FU）为继发的严重，潜在的威胁生命的毒性的遗传基础。为了实现这一目标，我们将a）继续进一步表征DPD缺乏症的药物遗传学综合征，b）表征了DPYD和BUP缺陷。 为了实现这些目标，我们将继续获取并利用来自5-FU治疗后IV级毒性的患者的生化和分子数据（例如酶活性，mRNA水平和分析嘧啶分解代谢基因的突变）。特别是，我们将研究：1）影响DPYD基因表达的其他转录调节元件的作用，包括识别a）与先前鉴定的启动子中调节元素I和II结合的转录因子，以及b）内含子1和3'-非互式区域中的其他潜在调节区域； 2） - 确定泛素（Ub） - 近发体系统在DPD蛋白调节中的作用 - a）确定野生型和突变体DPD蛋白的DPD蛋白半寿命，b）识别DPD蛋白的推定破坏性元素； 3）针对DPD缺乏症和嘧啶分解代谢途径的其他缺陷开发用户友好的诊断测试，包括a）表型测试和b）基因型测试； 4）其他因素的作用可能导致严重的5-FU毒性，包括5-FU作用位点的基因表达改变 - 胸苷酸合酶，b）变化的基因表达改变了合成代谢酶的基因表达，例如。尿苷和胸苷磷酸化酶以及激酶以及甲状腺磷酸化酶，以及c）其他分解代谢酶的基因表达改变，例如二氢嘧啶酶和bup。 GCRC资源的利用：护理和实验室人员已被利用至1）从5-FU有毒癌症患者中进行血液收集（截至350多个迄今350多个）2）进行药代动力学研究，检查5-FU毒性癌症患者的5-FU毒性癌症患者的嘧啶分解代谢（每名患者8个小时）（迄今为止的25例患者；以及5-FU有毒，DPD缺乏，DPYS缺乏症和BUP缺乏受试者/癌症患者的成纤维细胞的维持。研究人群和结果：该研究项目的成功进展应转化为未来接受氟吡啶药物的患者的改善护理。