COBRE: CREIGHTON: PILOT 3:ERBB2& UV IRRADIATION IN SKIN CARCINOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议中描述的研究旨在表征erbB2在细胞免疫应答中的作用 皮肤受到紫外线辐射(UV)。ErbB受体酪氨酸激酶，包括孤儿受体erbB2，是 已知能调节皮肤中的各种过程。初步数据表明，废除erbB2 结果：(1)角质形成细胞增殖减少，细胞周期停滞于G2/M期；(2)角质形成细胞增殖增加 培养的角质形成细胞和皮肤中的细胞凋亡，以及(3)增加紫外线诱导的细胞凋亡。我们建议 提示erbB2是角质形成细胞保护性反应的重要负性调节因子。描述了 ErbB2在皮肤对紫外线照射的反应中的作用尤其重要，因为紫外线(在 已知会导致非黑色素瘤皮肤癌，这是美国最常见的癌症 各州。紫外线是一种完全的致癌物，会造成DNA损伤，并促进克隆扩张 DNA损伤的细胞形成肿瘤。因为过度表达erb2会导致自发性皮肤肿瘤 ErbB2信号伙伴表皮生长因子受体的形成与消亡 为了减少皮肤肿瘤的生长，我们认为erbB2促进了UVR诱导的皮肤肿瘤的生长。 利用erbB2缺失和野生型角质形成细胞和皮肤移植方案，我们计划验证我们的假设 ErbB2调节皮肤对紫外线的反应，并参与紫外线诱导的皮肤癌的发生。 此外，这些研究将确定是否对erbB2信号进行调制是合适的 皮肤癌预防或治疗的靶点。具体目标包括1)通过以下方式确定机制 哪种erbB2影响角质形成细胞对紫外线的反应2)测量erbB2 增加紫外线诱导的皮肤肿瘤从启动角质形成细胞的生长。

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.