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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本提案中描述的研究旨在描述erbB 2在以下反应中的作用： 皮肤紫外线辐射（UV）。erbB受体酪氨酸激酶，包括孤儿受体erbB 2， 已知调节皮肤中的各种过程。初步数据显示，erbB 2基因的缺失 结果：（1）角质形成细胞增殖减少，G2/M期细胞周期停滞，（2）角质形成细胞增殖增加， 在培养的角质形成细胞和皮肤中的细胞凋亡，和（3）增加UV诱导的细胞凋亡。我们提出 erbB 2是角质形成细胞保护性反应的重要负调节因子。表征 erbB 2在皮肤对UV暴露的反应中的作用是特别重要的，这是因为UV（在皮肤中）对皮肤的刺激作用是非常重要的。 太阳光的一种形式）被认为会导致非黑色素瘤皮肤癌，这是美国最常见的癌症 States.紫外线是一种完全的致癌物质，会导致DNA损伤，并促进 DNA受损的细胞形成肿瘤。由于erbB 2的过度表达导致自发性皮肤肿瘤 erbB 2信号伴侣EGFR（表皮生长因子受体）消除时的形成 减少皮肤肿瘤的生长，我们认为erbB 2促进了紫外线诱导的皮肤肿瘤的生长。 利用erbB 2无效和野生型角质形成细胞和皮肤移植方案，我们计划测试我们的假设， erbB 2调节皮肤对UV的反应并促进UV诱导的皮肤致癌作用。 此外，这些研究将确定是否erbB 2信号的调制是适当的， 用于皮肤癌预防或治疗靶点。具体目标包括：1）确定机制， 其中erbB 2影响角质形成细胞对UV的反应，以及2）测量erbB 2 增加紫外线诱导的皮肤肿瘤生长从启动角质形成细胞。

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.