The long-term objective of this proposal is to begin to understand the mechanism of UVB-induced skin cancer. Cancers of the skin are the predominant cancer diagnosed in the United States. In addition to the trauma skin cancer causes for its victims, the treatment of skin cancer is also a tremendous burden financially on our healthcare system. Although it is known that the principle carcinogen responsible for the generation of skin cancer is the UV component of sunlight, very little is known about the exact relationship between UV- exposure and the development of skin cancer. The activation of the insulin-like growth factor-1 receptor (IGF-1R) was shown to be a critical factor in determining how keratinocytes respond to UVB exposure. UVB exposure in the presence of activated IGF-1Rs permits keratinocytes to remain viable and not undergo apoptosis. However, a consequence of continued viability is that the irradiated keratinocytes lose the capacity to replicate. We define these two functions of the IGF- 1R in response to IJVB exposure as the induction of survival and senescence. In contrast, in the absence of IGF-1 binding, the same UVB exposure will result in the induction of apoptosis. A critical feature in this model is that in the absence of IGF-1R activation, keratinocytes that survive UVBitradiation still maintain the potential to proliferate. It is this proliferation, following UVB-induced DNA damage that may produce keratinocytes that have oncogenic potential In this proposal, we will begin to characterize the mechanism of how the IGF-1R protects normal human keratinocytes from UVB-induced apoptosis. This characterization will be accomplished through the creation of a model system, which will selectively and specifically inactivate the activity of the IGF-1 R. This model system will be used to identify key components of the IGF-1R mediated, UVB-response in human keratinocytes. Through the identification of these components of the UVB-response in human keratinocytes, therapeutic strategies for the prevention of LTVB-induced carcinogenesis can be developed.
|Effective start/end date||9/1/01 → 6/30/06|
- National Institutes of Health: $284,500.00
- National Institutes of Health: $291,279.00
- National Institutes of Health: $286,765.00
- National Institutes of Health: $289,025.00
- Environmental Science(all)