Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents such as mitomycin C (MMC) and diepoxybutane (DEB) (Auerbach 1993), bone marrow (BM) failure, diverse congenital anomalies, and a marked increased in the incidence of malignancies. Eight complementation groups (FA-A through FA-H) have been identified. The human genes defected in the FA-C, FA- A FA-G groups were recently cloned. Fancc-deficient mice have been created by targeted mutations of the murine Fancc gene. Cells from France -/- mice showed hypersensitivity to MMC and DEB. Surprisingly, however, no gross hematologic defects or congenital anomalies were detected, although the homozygous mice showed decreased fertility. Evidence has been collected indicating that certain cytokines are involved in Fanconi anemia. TNF-alpha and IFN-gamma are inhibitory cytokines that can induced deregulated. Progenitor growth and apoptosis in Fancc-/- hematopoietic progenitor cells (HPC). FANCC transgene protected HPC FANCC transgene protected HPC from Fas-mediated apoptosis. IL-6, TNF-alpha and IFN-gamma, among others, are known to mediate immune-neuro-endocrine interactions. More recently, multiple endocrine abnormalities were discovered in FA patients, including deficiencies in growth hormone, thyroid and gonads function. We hypothesize that the endocrine abnormalities be due to aberrant response to cytokines, particularly TNF-alpha and IFN-gamma, in the endocrine glands. The proposed project will use Fancc-deficient mice and cell lines derived from endocrine glands, along with certain cytokines, to test this hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
National Research Service Awards for Senior Fellows (F33)
Project #
5F33HL010458-02
Application #
6402758
Study Section
Special Emphasis Panel (ZRG1-HEM-2 (02))
Program Officer
Werner, Ellen
Project Start
2001-07-21
Project End
Budget Start
2001-08-21
Budget End
2002-08-20
Support Year
2
Fiscal Year
2001
Total Cost
$49,412
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065