UVR-INDUCED SYSTEMIC EFFECTS AND MELANOMA INDUCTION

紫外线引起的系统效应和黑色素瘤诱导

• 批准号: 3202548
• 负责人: RONALD D LEY
• 金额: $ 7.44万
• 依托单位: LOVELACE RESPIRATORY RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-11 至 1995-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3202548
• 关键词: DNA damage; DNA repair; chemical carcinogen; chemical carcinogenesis; cornea disorder; eye neoplasms; melanoma; neoplastic process; opossums; photoactivation; pyrimidine dimers; radiation carcinogenesis; radiation dosage; radiation immunosuppression; solar radiation; ultraviolet radiation

Skin and eyes are the only organs of the body that are exposed directly to solar ultraviolet radiation (UVR). Sunlight causes many adverse effects which include cancers of the skin and a reduced visual acuity. The prospect of stratospheric ozone depletion and the accompanying increase in human exposure to UVR makes it imperative that we understand the detrimental effects of acute and chronic exposure to UVR. Because systemic effects which include immune suppression are involved in UVR- induced carcinogenesis, it is of considerable interest to delineate the extent to which systemic effects may be a factor in the carcinogenic process. The marsupial Monodelphis domestica is an experimental animal model uniquely suited for these studies because: 1) this animal, unlike rodents, has been shown to be susceptible to UVR-induced melanoma; 2) low cutaneous doses of UVR induce systemic effects in the form of immune suppression and enhanced susceptibility to UVR-induced corneal tumors; and, 3) the photoreactivation repair pathway active in M domestica, but not in rodents, can be used to study the role of pyrimidine dimers in DNA in UVR-induced cancer and systemic effects. Recent studies with M domestica showed that UVR-induced systemic effects significantly accelerated the appearance of UVR-induced corneal tumors. Furthermore, photoreactivation studies have shown that UVR-induced cutaneous and/or corneal DNA damage are involved in the induction of corneal tumors. The studies proposed herein will: 1) determine dose- response relationships for the capacity of cutaneous UVR exposures to accelerate the appearance of UVR-induced corneal tumors in M domestica; 2) determine whether UVR-induced local and systemic effects will alter the progression of chemically-induced melanocytic lesions to frank melanotic tumors; and, 3) determine with the photorepair pathway found in marsupials the relative importance of pyrimidine dimers in cutaneous and corneal DNA on the time to appearance of UVR-induced corneal cancers. These proposed studies will aid in elucidating a multi-faceted role for DNA damage in the carcinogenic process.

皮肤和眼睛是身体唯一直接暴露的器官 太阳紫外线辐射（UVR）。 阳光导致许多不利的 其影响包括皮肤癌和视力下降。 平流层臭氧消耗的前景及伴随的问题 人类暴露于紫外线辐射的增加使我们必须了解 急性和慢性暴露于紫外线辐射的有害影响。 因为 紫外线辐射对全身的影响包括免疫抑制， 诱导的致癌作用，这是相当感兴趣的描绘， 全身效应可能是致癌因素的程度 过程 有袋类动物Monodelphis arctica是一种实验动物， 模型特别适合这些研究，因为：1）这种动物，不像 啮齿类动物，已被证明对紫外线诱导的黑色素瘤易感; 2）低 皮肤剂量的UVR以免疫形式诱导全身效应， 抑制和增强对UVR诱导的角膜肿瘤的易感性; 和，3）光复活修复途径在M. 不在啮齿动物中，可用于研究嘧啶二聚体在DNA中的作用 紫外线诱发的癌症和全身效应。 最近的研究表明，紫外线诱导的全身效应， 显著加速了UVR诱导的角膜肿瘤的出现。 此外，光复活研究表明，紫外线诱导的 皮肤和/或角膜DNA损伤参与诱导 角膜肿瘤 本文提出的研究将：1）确定剂量- 皮肤UVR暴露能力的反应关系， 加速UVR诱导的角膜肿瘤的出现; 2)确定UVR诱导的局部和全身效应是否会改变 化学诱导的黑素细胞病变进展到弗兰克 黑色素瘤;和，3）确定与光修复途径发现 在有袋类动物中，嘧啶二聚体在皮肤 和角膜DNA对UVR诱导的角膜癌出现时间的影响。 这些拟议的研究将有助于阐明一个多方面的作用， 致癌过程中的DNA损伤。