Fanconi's Anemia (FA) is a genetic disorder manifesting with typical congenital malformations, childhood onset progressive bone marrow failure and increased cancer risk. 13 genes responsible for FA have been cloned and together constitute the FA/BRCA pathway which functions to maintain genome stability and to ensure stem cell survival. This Program Project will use a multidisciplinary approach to dissecting the molecular pathophysiology of FA and to use this knowledge to enhance therapy for FA, especially small molecule intervention. The clinical disciplines represented by the investigators include pediatrics, medical genetics, hematology and oncology. The scientific areas of expertise include stem cell biology, DNA repair, molecular hematology, zebra fish genetics, mouse genetics, cytogenetics, gene therapy and drug discovery. Core A will use cell-based assays to screen for novel compounds and genes that positively impact the phenotypes of FA cells. New drugs discovered by screening and others derived from insights into pathophysiology will be systematically evaluated in all 3 projects. Project 1 uses zebrafish models of FA, projects 2 and 3 use FA knockout mice as well as pluripotent stem cells from human FA patients. These IPS cells generated by direct reprogramming will be provided by Core C. Cytogenetic abnormalities are a key feature of FA and Core B will provide support in this area. In addition to drug screening the projects will study genetic interactions of the FA/BRCA pathway, work on the non-canonical roles of FA proteins and explore gene repair as a novel approach for gene therapy in the disease.

Public Health Relevance

The significance of this Program Project is multifold in that therapeutic benefits for FA patients are likely. In addition, however, the work will shed light on generally important processes such as the maintenance of hematopoietic stem cells in the face of damage, leukemogenesis and the action of synthetic androgens in stem cells. Furthermore, drugs that benefit bone marrow failure and delay cancer in FA may well useful in other forms of aplastic anemia and cancer.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048546-19
Application #
8469329
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Qasba, Pankaj
Project Start
1997-07-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
19
Fiscal Year
2013
Total Cost
$1,944,635
Indirect Cost
$681,885
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Whiteaker, Jeffrey R; Zhao, Lei; Ivey, Richard G et al. (2018) Targeted mass spectrometry enables robust quantification of FANCD2 mono-ubiquitination in response to DNA damage. DNA Repair (Amst) 65:47-53
Kroeger Jr, Paul T; Drummond, Bridgette E; Miceli, Rachel et al. (2017) The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 428:148-163
Rondinelli, Beatrice; Gogola, Ewa; YĆ¼cel, Hatice et al. (2017) EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol 19:1371-1378
Karras, Georgios I; Yi, Song; Sahni, Nidhi et al. (2017) HSP90 Shapes the Consequences of Human Genetic Variation. Cell 168:856-866.e12
Mouw, Kent W; Goldberg, Michael S; Konstantinopoulos, Panagiotis A et al. (2017) DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov 7:675-693
Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney et al. (2016) Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. J Leukoc Biol 99:455-65
Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew et al. (2016) Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood 128:2774-2784
Zhang, Haojian; Kozono, David E; O'Connor, Kevin W et al. (2016) TGF-? Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell 18:668-81
Zhang, Qing-Shuo; Benedetti, Eric; Deater, Matthew et al. (2015) Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Reports 4:90-102
Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D et al. (2015) Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers. Clin Cancer Res 21:1962-72

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