Ultraviolet B (UVB, 29O-320nm), a component of natural sunlight, causes a selective immunosuppression which appears to be a critical risk factor for UV carcinogenesis and which may impact on the course of certain infectious diseases. We have identified in mice a genetically determined susceptibility to immunosuppression by UVB and have developed a model for autosomal and X-linked genetic control of susceptibility to UV immunosuppression.
Our specific aims are directed toward confirmation of this model and identification and cloning of the genes responsible. Our strategy is to approach this question using genetically defined strains of mice to define the parameters of the in vivo phenotype and to characterize gene action by techniques of molecular biology. The combination of these two approaches is necessary to understanding control of UV suppression at the phenotypic level and at the molecular level. We have produced a congenic strain for one of the autosomal genes which has enabled us to isolate the action of this gene for high and low susceptibility to UV immunosuppression and will permit its identification and cloning Establishment of genetic linkage is a necessary prerequisite to gene identification for this complex phenotype.
The specific aims are l) testing of the model for genetic control of susceptibility to UV immunosuppression, 2) complete derivation and testing of a strain of mice congenic for a major dominant autosomal gene regulating high susceptibility to UV immunosuppression, 3) establish genetic linkage of the major dominant autosome gene and 4) identify the autosomal gene using Differential Display cloning. Cloning and sequencing the genes controlling UV suppression will enable identification of homologous loci in the human genome. Further, our unique finding of genetic control of UV suppression by autosomal and X- linked genes can be used as a model for testing for similar control mechanisms in humans. A genetically determined high susceptibility to the immunosuppressive effects of Uv radiation may be a highly significant risk factor for a significant number of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053765-08
Application #
2700450
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Pelroy, Richard
Project Start
1990-12-04
Project End
2000-03-31
Budget Start
1998-05-01
Budget End
2000-03-31
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
George Washington University
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Wolnicka-Glubisz, Agnieszka; De Fabo, Edward; Noonan, Frances (2013) Functional melanocortin 1 receptor Mc1r is not necessary for an inflammatory response to UV radiation in adult mouse skin. Exp Dermatol 22:226-8
Noonan, Frances P; Zaidi, M Raza; Wolnicka-Glubisz, Agnieszka et al. (2012) Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun 3:884
Zaidi, M Raza; Davis, Sean; Noonan, Frances P et al. (2011) Interferon-? links ultraviolet radiation to melanomagenesis in mice. Nature 469:548-53
Wolnicka-Glubisz, Agnieszka; Damsker, Jesse; Constant, Stephanie et al. (2007) Deficient inflammatory response to UV radiation in neonatal mice. J Leukoc Biol 81:1352-61
Wolnicka-Glubisz, Agnieszka; Noonan, Frances P (2006) Neonatal susceptibility to UV induced cutaneous malignant melanoma in a mouse model. Photochem Photobiol Sci 5:254-60
De Fabo, Edward C; Noonan, Frances P; Fears, Thomas et al. (2004) Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res 64:6372-6
Noonan, Frances P; Muller, H Konrad; Fears, Thomas R et al. (2003) Mice with genetically determined high susceptibility to ultraviolet (UV)-induced immunosuppression show enhanced UV carcinogenesis. J Invest Dermatol 121:1175-81
Clemens, K E; Churchill, G; Bhatt, N et al. (2000) Genetic control of susceptibility to UV-induced immunosuppression by interacting quantitative trait loci. Genes Immun 1:251-9
Hart, P H; Grimbaldeston, M A; Hosszu, E K et al. (1999) Age-related changes in dermal mast cell prevalence in BALB/c mice: functional importance and correlation with dermal mast cell expression of Kit. Immunology 98:352-6
Bouscarel, B; Noonan, F; Ceryak, S et al. (1998) Regulation of stimulated cyclic AMP synthesis by urocanic acid. Photochem Photobiol 67:324-31

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