Ultraviolet B irradiation of human keratinocytes

这项建议的长期目标是开始了解UVB诱发皮肤癌的机制。皮肤癌是美国诊断出的主要癌症。除了皮肤癌给患者造成的创伤外，皮肤癌的治疗也给我们的医疗体系带来了巨大的经济负担。虽然众所周知，导致皮肤癌发生的主要致癌物质是阳光中的紫外线成分，但人们对紫外线暴露与皮肤癌发生的确切关系知之甚少。胰岛素样生长因子-1受体(IGF-1R)的激活被证明是决定角质形成细胞对UVB辐射的反应的关键因素。在激活的IGF-1RS存在的情况下，UVB暴露使角质形成细胞保持存活，不发生凋亡。然而，持续存活的结果是，受辐射的角质形成细胞失去了复制能力。我们将IGF-1R应对IJVB暴露的这两个功能定义为诱导存活和衰老。相反，在没有IGF-1结合的情况下，同样的UVB暴露将导致细胞凋亡的诱导。这个模型的一个关键特征是，在IGF-1R没有激活的情况下，在紫外线照射下存活的角质形成细胞仍然保持着增殖的潜力。正是这种增殖，伴随着UVB诱导的DNA损伤，可能产生具有致癌潜力的角质形成细胞。在这个提议中，我们将开始描述IGF-1R如何保护正常的角质形成细胞免受UVB诱导的细胞凋亡的机制。这一特征将通过创建一个模型系统来完成，该模型系统将选择性和特异性地灭活IGF-1R的活性。该模型系统将用于识别IGF-1R介导的UVB-角质形成细胞反应的关键成分。通过鉴定人角质形成细胞中UVB反应的这些成分，可以开发出预防LTVB诱导的致癌的治疗策略。

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.