Grants and Contracts Details
Description
We are interested in deciphering the molecular basis of UV injury and carcinogenesis in the skin, with the longterm
research objective of designing chemoprotective strategies against skin cancer. Fair skin correlates with
enhanced expression of pheomelanin, a pigment with poor UV-blocking abilities, and reduced expression of
eumelanin, a pigment with excellent UV-blocking properties. Logically, pheomelanotic individuals endure the
highest incidence of UV-mediated damage, including skin cancer. Pigmentation is regulated by the binding of
melanocortin stimulating hormone (MSH) to its cognate receptor, the melanocortin-1 receptor (MC1 R), which in
turn mediates adenylyl cyclase activation and subsequent production of cyclic AMP (cAMP). High functioning
MC1 R variants result in high levels of cAMP and eumelaninization, whereas low functioning MC1 R variants
lead to low levels of cAMP and pheomelanization. We have developed a novel mouse model that mimics
human skin of different pigmentation (eumelanotic, pheomelanotic, and albino). We found that by topically
applying a small molecule (forskolin) to the fair-skinned animals, eumelanin production was induced and the
animals were UV-protected. Such forskolin-mediated eumelanin production likely occurs by directly activating
adenylyl cyclase in melanocytes, thereby "by-passing" the defective MC1 R signaling that causes fair skin in our
model. We hypothesize that MC1 R dysfunction leads to UV-dependent oxidative damage in the skin and
defective repair of UV-mediated DNA damage. Further, we propose that topical forskolin protects against UV
injury through eumelanin induction and rescue of DNA repair. Taking advantage of our unique murine model,
we will determine the effect of pheomelanin on UV damage in the skin (Aim 1), and define the contribution of
MC1 R function in the repair of UV-mediated damage (Aim 2). In our studies, we will measure different types of
UV-induced oxidative damage, analyze repair of this damage, and determine whether topical forskolin can
modify these damage and repair profiles. Our findings will have significant health relatedness, as they will
clarify longstanding questions regarding pheomelanin in oxidative damage and MC1 R function in the repair of
UV-induced damage. Most importantly, we anticipate that our resulting data will provide clear insight into
effective, topical approaches to repairing UV-mediated skin damage and preventing skin cancer.
Status | Finished |
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Effective start/end date | 8/1/07 → 7/31/09 |
Funding
- National Cancer Institute: $146,500.00
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