Genetic Polymorphism of Dihydropyrimidine Dehydrogenase

Project: Research project

Project Details


DESCRIPTION (provided by applicant): 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) and
in particular further characterize the pharmacogenetic syndrome of
dihydropyrimidine dehydrogenase (DPD) deficiency. During the next grant period
we will further clarify the molecular mechanisms of regulation of the gene
responsible for expression of DPD (DPYD), the role of the ubiquitin-proteasome
system in DPD protein turnover, develop phenotypic and genotypic diagnostic
tests for DPD deficiency, and lastly examine the role of other enzymatic steps
in 5-FU metabolism in the cause of severe 5-FU toxicity. In approaching each of
the specific aims listed below, we will continue to obtain and utilize
biochemical and molecular data (e.g., DPD enzyme activity, DPD mRNA level, and
analysis for mutations in DPYD gene) from patients presenting with grade IV
toxicity after 5-FU therapy. The specific aims will include: Spec. Aim 1) -
Identify and clarify 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 intron 1
and the 3'-untranslated region; Spec. Aim 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; Spec. Aim 3) -
Develop user-friendly diagnostic tests for DPD deficiency including a)
phenotypic tests of DPD deficiency suitable for routine screening, and b)
genotypic tests for specific causes of DPD deficiency; and Spec. Aim 4) -
Determine the role of other factors that 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. Successful progress on this research project should
translate into improved care for patients receiving fluoropyrimidine drugs in
the future.
StatusNot started


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