Ultraviolet B irradiation of human keratinocytes

这项提案的长期目标是开始了解UVB诱发皮肤癌的机制。皮肤癌是美国诊断的主要癌症。除了皮肤癌给受害者带来的创伤外，皮肤癌的治疗也是我们医疗保健系统的巨大经济负担。虽然已知导致皮肤癌产生的主要致癌物是阳光中的紫外线成分，但对紫外线暴露与皮肤癌发展之间的确切关系知之甚少。胰岛素样生长因子-1受体（IGF-1 R）的激活被证明是决定角质形成细胞如何响应UVB暴露的关键因素。在活化的IGF-1 Rs存在下的UVB暴露允许角质形成细胞保持活力并且不经历凋亡。然而，持续活力的结果是照射的角质形成细胞失去复制能力。我们定义这两个功能的IGF-1 R在响应IVB暴露的诱导生存和衰老。相反，在IGF-1结合的情况下，相同的UVB暴露将导致细胞凋亡的诱导。该模型的一个关键特征是，在缺乏IGF-1 R活化的情况下，在紫外线照射下存活的角质形成细胞仍然保持增殖的潜力。正是这种增殖，UVB诱导的DNA损伤，可能会产生角质形成细胞，具有致癌潜力在这个建议中，我们将开始的特点，IGF-1 R如何保护正常人角质形成细胞从UVB诱导的凋亡的机制。该表征将通过创建模型系统来完成，该模型系统将选择性地和特异性地鉴定IGF-1 R的活性。该模型系统将用于识别IGF-1 R介导的人角质形成细胞UVB反应的关键组分。通过鉴定人角质形成细胞中UVB反应的这些组分，可以开发用于预防LTVB诱导的致癌作用的治疗策略。

The long-term objective of this proposal is to begin to understand the mechanism of UVB-induced skin cancer. Cancers of the skin are the predominant cancer diagnosed in the United States. In addition to the trauma skin cancer causes for its victims, the treatment of skin cancer is also a tremendous burden financially on our healthcare system. Although it is known that the principle carcinogen responsible for the generation of skin cancer is the UV component of sunlight, very little is known about the exact relationship between UV- exposure and the development of skin cancer. The activation of the insulin-like growth factor-1 receptor (IGF-1R) was shown to be a critical factor in determining how keratinocytes respond to UVB exposure. UVB exposure in the presence of activated IGF-1Rs permits keratinocytes to remain viable and not undergo apoptosis. However, a consequence of continued viability is that the irradiated keratinocytes lose the capacity to replicate. We define these two functions of the IGF- 1R in response to IJVB exposure as the induction of survival and senescence. In contrast, in the absence of IGF-1 binding, the same UVB exposure will result in the induction of apoptosis. A critical feature in this model is that in the absence of IGF-1R activation, keratinocytes that survive UVBitradiation still maintain the potential to proliferate. It is this proliferation, following UVB-induced DNA damage that may produce keratinocytes that have oncogenic potential In this proposal, we will begin to characterize the mechanism of how the IGF-1R protects normal human keratinocytes from UVB-induced apoptosis. This characterization will be accomplished through the creation of a model system, which will selectively and specifically inactivate the activity of the IGF-1 R. This model system will be used to identify key components of the IGF-1R mediated, UVB-response in human keratinocytes. Through the identification of these components of the UVB-response in human keratinocytes, therapeutic strategies for the prevention of LTVB-induced carcinogenesis can be developed.