COBRE: CREIGHTON: P2:ERBB2& UV IRRADIATION IN SKIN CARCINOGENESIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该提案中描述的研究旨在表征erbB 2在皮肤对紫外线辐射（UV）的反应中的作用。已知erbB受体酪氨酸激酶，包括孤儿受体erbB 2，调节皮肤中的多种过程。初步数据表明，erbB 2的废除导致：（1）角质形成细胞增殖减少和G2/M期细胞周期停滞，（2）培养的角质形成细胞和皮肤中的凋亡增加，和（3）UV诱导的凋亡增加。我们建议，erbB 2是一个重要的负调节角质形成细胞的保护反应。描述erbB 2在皮肤对紫外线暴露的反应中的作用尤其重要，因为已知紫外线（以阳光的形式）会导致非黑色素瘤皮肤癌，这是美国最常见的癌症。紫外线是一种完全的致癌物质，导致DNA损伤，并促进DNA损伤细胞的克隆扩增形成肿瘤。由于过度表达erbB 2导致自发性皮肤肿瘤形成，而废除erbB 2信号伴侣EGFR（表皮生长因子受体）减少皮肤肿瘤生长，我们建议erbB 2促进紫外线诱导的皮肤肿瘤的生长。利用erbB 2空和野生型角质形成细胞和皮肤移植协议，我们计划测试我们的假设，即erbB 2调节皮肤对UV的反应，并有助于UV诱导的皮肤致癌。此外，这些研究将确定erbB 2信号转导的调节是否是皮肤癌预防或治疗的适当靶点。具体目的包括：1）确定erbB 2影响角质形成细胞对UV的反应的机制; 2）测量erbB 2增加UV诱导的角质形成细胞皮肤肿瘤生长的程度。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 the skin to ultraviolet radiation (UV). erbB receptor tyrosine kinases, including the orphan receptor erbB2, are known to regulated a variety of processes in the skin. Preliminary data have shown that abrogation of erbB2 results in: (1) decreased proliferation and a G2/M-phase cell cycle arrest in keratinocytes, (2) increased apoptosis in cultured keratinocytes and in the skin, and (3) increased UV-induced apoptosis. We propose that erbB2 is an important negative regulator of the protective response of keratinocytes. Characterizing the role of erbB2 in the skin's response to UV-exposure is especially important due to the fact that UV (in the form of sunlight) is known to cause non-melanoma skin cancer, the most common cancer in the United States. UV is a complete carcinogen, causing DNA damage as well as promoting the clonal expansion of DNA-damaged cells to form tumors. Since overexpression of erbB2 results in spontaneous skin tumor formation 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 hypothesis that 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 appropriate target for skin cancer prevention or treatment. The Specific Aims include 1) determining the mechanisms by which erbB2 influences the response of keratinocytes to UV and 2) measuring the extent to which erbB2 increases UV-induced skin tumor growth from initiated keratinocytes.