Grants and Contracts Details
Our long-term objectives are to (1) understand how melanocortin 1 receptor (MC1R) activity modulates UV- mediated DNA damage and repair, (2) design targeted/rational strategies that rescue defective MCi R function, and (3) effectively prevent melanoma. In our parent grant, we hypothesized up-regulation of cAMP (the second messenger for MCi R signalling) would protect the skin from UV-mediated damage by promoting the synthesis of UV-protective eumelanin and enhancing DNA damage repair. Based on this hypothesis, we proposed three aims: (1) Characterize the role of MC1R in UV-mediated oxidative damage, and whether pharmacologic replacement of MCI R before UV exposure protects against oxidative damage; (2) Explore the role of MCi R function in the repair of UV-induced lesions: and (3) Determine whether pharmacologic replacement of MCi R (via forskolin) immediately following IJV exposure enhances the repair of oxidative and direct DNA damage. In the parent grant, our analyses explored MCi R function and UV effects almost exclusively in whole skin samples, which preclude more in depth mechanistic studies. As we have recently developed the ability to culture melanin-producing primary melanocytes (the skin cell from which melanoma derives) from our genetically-defined murine model of human skin, we are now well- positioned to address long-standing questions regarding MC1R function and melanomagenesis. We have made signicant progress on Aims 1 and 2, which involve whole skin and cultured melanocyte analyses, but have not yet begun the Aim 3 studies, which exclusively use whole skin samples. Thus, as an extension of Aim 3, we propose three new subaims. Following UV-exposure we will treat melanocytes with forskolin, and analyze (I) oxidative damage and resolution of indirect DNA damage (flow cytometry, comet assay, TBAR assay, southwestern analysis, and GC/MS), (2) direct DNA damage repair and regulation of nucleotide excision repair proteins (flow cytometry, southwestern and western analyses, RT-PCR, and promoter activation studies), and (3) mutation incidence (HPRT assay). The proposed subaims complement the research thrust of Aims 1 and 2 of the parental grant, and represent a logical molecular extension of Aim 3.
|Effective start/end date||8/1/09 → 7/31/10|
- National Cancer Institute: $112,794.00
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