Non-melanoma skin cancer: A model for impact of aging on an environmental disease

非黑色素瘤皮肤癌：衰老对环境疾病影响的模型

• 批准号: 9204120
• 负责人: DAVID RINSEY BICKERS
• 金额: $ 12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204120
• 关键词: 2 year old; Acute; Address; Adult; Age; Age-Years; Aging; Alleles; Animal Housing; Animals; Apoptotic; Basal cell carcinoma; Belief; Benchmarking; Biological Markers; Breeding; Cells; Chronic; Cleaved cell; Communities; Cutaneous; DNA Adducts; DNA Repair Enzymes; Defect; Development; Diagnosis; Disease; Elderly; Exposure to; Female; Gender; Genotype; Histopathology; Human; Immunologic Markers; Inbred HRS Mice; Incidence; Inflammatory Response; Laboratories; Life; Malignant Neoplasms; Modeling; Molecular; Mus; Outcome; Pathogenesis; Phase; Population; Pre-Clinical Model; Predisposition; Protocols documentation; Radiation induced damage; Radiation-Induced Cancer; Recording of previous events; Research; Risk Factors; S-Phase Fraction; Signal Pathway; Signal Transduction; Skin; Skin Aging; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Solar Energy; Squamous cell carcinoma; Structure; Sun Exposure; Sunlight; Testing; Therapeutic; Time; Tissues; Tumor Burden; Ultraviolet B Radiation; Ultraviolet Rays; age effect; age related; aged; base; clinically relevant; cohort; cost; design; in vivo; innovation; insight; juvenile animal; male; mouse model; new therapeutic target; pre-clinical; skin squamous cell carcinoma; tumor; young adult

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common forms of human cancer with more than 5 million cases diagnosed in the US each year. The incidence of NMSC has increased 200% over the past three decades in the US and half of all adults who live to age 65 will develop skin cancer at least once. It is widely accepted that sunlight-derived ultraviolet radiation (UVR) and advanced age are the major risk factors for NMSC. Thus NMSC incidence is 50 to 300 times higher in adults aged 75 and older compared to those under 45 years of age. Approximately, 90% of NMSC in humans are associated with exposure to sunlight-derived UVR and the major carcinogenic components of solar UVR include UVB (290-320nm) and UVA (320-400nm). Mouse models such as SKH-1 hairless mice have been studied extensively using experimental platforms that mimic exposure to these wavelengths and have facilitated our understanding of the acute and chronic effects of UVR skin damage at the cellular and molecular level. However, the impact of aging per se and its influence on susceptibility to UVR-induced NMSC has been largely overlooked by the research community, likely due to the unavailability of older animals as well as the high costs and time associated with housing animals at ages of 2 years or greater. It is our belief that in vivo skin cancer studies conducted in young mice are unlikely to address the pathogenesis of environmentally-induced human skin cancer. As such, our severe lack of understanding of age-related alterations of skin structure and function and their impact on tumor susceptibility represents a key gap in the skin cancer field. This UH2/UH3 application aims to address this key gap by testing the hypothesis that Aged murine skin is more susceptible to UVR- induced skin damage and NMSC compared to young adult skin. To test our hypothesis, we will employ SKH- 1 and Ptch1+/-/SKH-1 mice, which are well established pre-clinical models for UVR-induced SCC and BCC, respectively. During the UH2 phase, we will establish cohorts of young and aged SKH-1 and Ptch1+/-/SKH-1 mice for UVR studies as well as experimental benchmarks for UVR-induced skin defects in young and aged mouse skin. During the UH3 phase, we will conduct chronic and acute UVR studies to determine whether age impacts susceptibility to UVR-induced skin defects and NMSC. It is our belief that our SKH-1 and Ptch1+/-/SKH- 1 models will firmly establish clinical relevance for UVR-induced NMSC studies in aged mice and impact the cancer field by signifying a need to shift mechanism- and therapeutic-based research to aged mouse models in order to more closely approximate the history of sun exposure and its consequences in the human population and to better identify novel targeted therapies for age-related NMSCs.

非黑色素瘤皮肤癌（NMSC），包括基底细胞癌（BCC）和鳞状细胞癌 （SCC）是人类癌症的最常见形式，在美国诊断出超过500万例 年。在过去的三十年中，NMSC的发病率在美国和所有成年人中有一半增加了200％ 活到65岁的人将至少患上皮肤癌。阳光来源的紫外线已被广泛接受 辐射（UVR）和高龄是NMSC的主要危险因素。因此，NMSC的发病率是50至300次 与45岁以下的年龄相比，年龄较高的成年人年龄较高。大约是NMSC的90％ 人类与暴露于阳光衍生的UVR和太阳能的主要致癌成分有关 UVR包括UVB（290-320nm）和UVA（320-400nm）。鼠标模型，例如SKH-1无毛老鼠 使用模仿暴露于这些波长的实验平台进行了广泛的研究，并有助于 我们对细胞和分子水平上UVR皮肤损伤的急性和慢性作用的理解。 但是，衰老本身的影响及其对UVR诱导的NMSC易感性的影响很大 研究界忽略了研究界，可能是由于老年动物的无法获得以及高昂的成本 与2岁或更高年龄的住房动物相关的时间。我们相信体内皮肤癌 在年轻小鼠中进行的研究不太可能解决环境诱导的人的发病机理 皮肤癌。因此，我们严重缺乏对年龄相关的皮肤结构和功能改变的了解 它们对肿瘤易感性的影响代表了皮肤癌领域的关键差距。此UH2/UH3应用程序 旨在通过测试陈年鼠皮更容易受到UVR-的假设来解决这一关键差距 与年轻的成人皮肤相比，诱导皮肤损伤和NMSC。为了检验我们的假设，我们将采用SKH- 1和PTCH1+/ - /SKH-1小鼠，它们是UVR诱导的SCC和BCC的临床前模型， 分别。在UH2阶段，我们将建立年轻和老年SKH-1和PTCH1+/ - /SKH-1的队列 UVR研究的小鼠以及用于UVR诱导的年轻和老年皮肤缺陷的实验基准 鼠标皮肤。在UH3阶段，我们将进行慢性和急性UVR研究，以确定年龄是否 影响对UVR引起的皮肤缺陷和NMSC的敏感性。我们相信我们的SKH-1和PTCH1+/ - /SKH- 1模型将对在老年小鼠中对UVR诱导的NMSC研究建立临床相关性，并影响 癌症领域通过表示需要将基于机制和基于治疗的研究转移到老年小鼠模型中 为了更亲密地近似阳光的历史及其对人口的后果 并更好地识别针对年龄相关的NMSC的新型靶向疗法。