Chronic exposure of human to ultraviolet radiation (UVR) is known to cause photoaging (dermatoheliosis), non-melanoma skin cancer, and possibly melanoma.
The specific aims of this project are directed to demonstrate the: a) molecular nature of photoaging and biochemical approaches for its amelioration; b) role of UVR in the induction of melanoma; c) usefulness of new and potent chemicals to stimulate melanin pigmentation of angelicins, khellin, and synthetic alpha-MSH melanotrophins; d) role of reactive 02 species in cutaneous phototoxic reactions by psoralens; and e) role of cutaneous involving the alterations of collagen, glycosaminoglycans, elastin, and certain enzymes in hairless mice subjected to photoaging by repeated exposure to UVB and UVA radiation. Studies involve determination of Type I and III collagen, cross-links and collagen, changes in 4-OH-prolyl-4'- hydroxylase, lysyl hydroxylase, desmosine, isodesmosine, and proteoglycans and evaluation of the role of certain free radical scavengers and antioxidants (e.g., beta-carotene, alpha-tocopherol, ethyl sorbate, B-alanyl-l-histidine) in the prevention of amelioration of biochemical alterations in photoaging. In Project II, the cause-effect relationship evidenced by epidemiological data on the development of melanoma by UVR, will be substantiated by animal experimentation and irradiation with UVB and UVA, crude action spectrum studies, and histologic confirmation in two animal models (black guinea pigs and pigmented hairless mice) by first producing blue nevi by topical DMBA treatment and subsequent repeated exposures to UVB and UVA of blue nevus-like pigmented macules. In Project III, the usefulness and the mode of melanin pigmentation by new nonphototoxic furocoumarins, furancohromones, and potent synthetic melanotrophins for the possible treatment of patients with vitiligo will be evaluated. Project IV includes studies to elucidate the role of reactive in the pathogenesis of phototoxic reaction induced by psoralens + UVA and involves the determination of prostaglandins in the presence and absence of selective quenchers of reactive 02 and free radicals. In Project V, the age-related changes of SOD in humans skin biopsies and cultured human keratinocytes will be studied to demonstrated the importance of mammalian skin SOD in photoaging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA005003-34
Application #
3163195
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1975-05-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1994-08-31
Support Year
34
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Gonzalez, S; Pathak, M A (1996) Inhibition of ultraviolet-induced formation of reactive oxygen species, lipid peroxidation, erythema and skin photosensitization by polypodium leucotomos. Photodermatol Photoimmunol Photomed 12:45-56
Pathak, M A; Fitzpatrick, T B (1992) The evolution of photochemotherapy with psoralens and UVA (PUVA): 2000 BC to 1992 AD. J Photochem Photobiol B 14:3-22
Dalle Carbonare, M; Pathak, M A (1992) Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B 14:105-24
Husain, Z; Pathak, M A; Flotte, T et al. (1991) Role of ultraviolet radiation in the induction of melanocytic tumors in hairless mice following 7,12-dimethylbenz(a)anthracene application and ultraviolet irradiation. Cancer Res 51:4964-70
Pathak, M A (1991) Ultraviolet radiation and the development of non-melanoma and melanoma skin cancer: clinical and experimental evidence. Skin Pharmacol 4 Suppl 1:85-94
Carraro, C; Pathak, M A (1988) Studies on the nature of in vitro and in vivo photosensitization reactions by psoralens and porphyrins. J Invest Dermatol 90:267-75
Carraro, C; Pathak, M A (1988) Characterization of superoxide dismutase from mammalian skin epidermis. J Invest Dermatol 90:31-6
Zarebska, Z; Pathak, M A; Jarzabek-Chorzelska, M et al. (1987) Repair of UV-damaged DNA in mammalian skin followed by the immunohistochemical method. Acta Biochim Pol 34:93-102
Joshi, P C; Carraro, C; Pathak, M A (1987) Involvement of reactive oxygen species in the oxidation of tyrosine and dopa to melanin and in skin tanning. Biochem Biophys Res Commun 142:265-74
Pathak, M A (1987) Sunscreens and their use in the preventive treatment of sunlight-induced skin damage. J Dermatol Surg Oncol 13:739-50

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