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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项建议中描述的研究旨在表征erbB2在皮肤对紫外线辐射(UV)的反应中的作用。ErbB受体酪氨酸激酶，包括孤儿受体erbB2，已知调节皮肤中的各种过程。初步数据表明，取消erbB2导致：(1)角质形成细胞增殖减少，细胞周期G2/M期停滞，(2)培养的角质形成细胞和皮肤细胞凋亡增加，(3)紫外线诱导的细胞凋亡增加。我们认为，erbB2是角质形成细胞保护性反应的重要负性调节因子。确定erbB2在皮肤对紫外线照射的反应中的作用尤其重要，因为众所周知紫外线(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，会造成DNA损伤，并促进DNA损伤细胞的克隆性扩张形成肿瘤。由于erbB2的过度表达导致自发的皮肤肿瘤的形成，而erbB2信号伙伴EGFR(表皮生长因子受体)的缺失则抑制了皮肤肿瘤的生长，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，即erbB2调节皮肤对紫外线的反应，并有助于紫外线诱导的皮肤癌发生。此外，这些研究将确定是否调控erbB2信号是皮肤癌预防或治疗的合适靶点。其具体目标包括：1)确定erbB2影响角质形成细胞对紫外线反应的机制；2)测量erbB2促进紫外线诱导的皮肤肿瘤细胞从启动的角质形成细胞生长的程度。

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.