This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The research described in this proposal is designed to characterize the role of erbB2 in the response of theskin to ultraviolet radiation (UV). erbB receptor tyrosine kinases, including the orphan receptor erbB2, areknown to regulated a variety of processes in the skin. Preliminary data have shown that abrogation of erbB2results in: (1) decreased proliferation and a G2/M-phase cell cycle arrest in keratinocytes, (2) increasedapoptosis in cultured keratinocytes and in the skin, and (3) increased UV-induced apoptosis. We proposethat erbB2 is an important negative regulator of the protective response of keratinocytes. Characterizing therole of erbB2 in the skin's response to UV-exposure is especially important due to the fact that UV (in theform of sunlight) is known to cause non-melanoma skin cancer, the most common cancer in the UnitedStates. UV is a complete carcinogen, causing DNA damage as well as promoting the clonal expansion ofDNA-damaged cells to form tumors. Since overexpression of erbB2 results in spontaneous skin tumorformation while abrogation of the erbB2 signaling partner EGFR (epidermal growth factor receptor)decreases skin tumor growth, we propose that erbB2 promotes the growth of UVR-induced skin tumors.Utilizing erbB2 null and wild type keratinocytes and skin grafting protocols, we plan to test our hypothesisthat erbB2 regulates the response of the skin to UV and contributes to UV-induced skin carcinogenesis.Furthermore, these investigations will determine whether modulation of erbB2 signaling is an appropriatetarget for skin cancer prevention or treatment.
The Specific Aims i nclude 1) determining the mechanisms bywhich erbB2 influences the response of keratinocytes to UV and 2) measuring the extent to which erbB2increases UV-induced skin tumor growth from initiated keratinocytes.
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