The long term goal of research proposed in this Program Project is to provide a detailed description of the Werner syndrome protein (WRN) functional pathway in human somatic cells, and to determine how a loss of WRN function leads to the cellular and clinical phenotypes of Werner syndrome that include constitutional genetic instability and an elevated risk of cancer. The Werner Syndrome Program Project is an integrated research effort consisting of 4 Projects and 2 Cores that are collectively focused on the following questions: 1. what proteins and DNA substrates constitute the WRN functional pathway in human somatic cells? 2. what are the important physiologic functions of WRN in human somatic cells? 3. how does loss of WRN function lead to genetic instability, selective DNA damage hypersensitivity and cell proliferation defects? 4. what role do WRN polymorphisms and mutations play in promoting the risk or pathogenesis of cancer or other diseases in the general population? Results of the proposed research will delineate normal functions of the WRN protein in human somatic cells, and how the loss of function leads to pathogenesis of the Werner syndrome cellular and clinical phenotypes. Results of the proposed research will also indicate the potential importance of common heritable alterations in WRN expression---polymorphisms in, or loss of one active copy of, the WRN gene--in promoting cancer risk and pathogenesis in the general population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077852-08
Application #
7028953
Study Section
Subcommittee G - Education (NCI)
Program Officer
Okano, Paul
Project Start
2000-03-07
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$1,357,018
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627
Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334
Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202
Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42
Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285
Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89
Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383
Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6
Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081
Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114

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