Mechanisms of photocarcinogenesis in geriatric skin

老年皮肤光致癌机制

基本信息

批准号：
9064190
负责人：
DAN F SPANDAU
金额：
$ 35.1万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064190
关键词：
Acute Age Aging Apoptosis Biological Assay Biological Models Cell Culture Techniques DNA Damage Data Dermabrasion Dermal Development Effectiveness Elderly Elements Epidemiology Epidermis Excision Exposure to Fibroblasts Goals Growth Health Care Costs Healthcare Systems Human Immunodeficient Mouse In Vitro Incidence Individual Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Laboratories Lasers Lead Link Malignant Neoplasms Mediating Medicare Methods Morbidity - disease rate Mutation Neoplasms Newly Diagnosed Pathway interactions Patients Play Population Predisposition Prevention Production Proliferating Receptor Activation Receptor Signaling Rejuvenation Risk Risk Factors Role Signal Pathway Signal Transduction Pathway Skin Skin Aging Skin Cancer Skin Carcinoma Skin graft Sunlight Techniques Testing The Sun Therapeutic Time Tissue Model UV carcinogenesis UVB induced Ultraviolet B Radiation Ultraviolet Rays United States aged cancer survival cancer type carcinogenesis cost in vivo innovation irradiation keratinocyte monolayer mortality novel prevent prophylactic research study response restoration senescence skin organogenesis sun damage therapy design ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) has the highest incidence of all cancers in the United States. While rarely fatal, the treatment of NMSC is estimated to cost our healthcare system over a billion dollars annually. Therefore, the prevention rather than the excision of NMSC has the potential to have a major impact on healthcare costs. While it is clear that exposure to the ultraviolet components in sunlight (specifically UVB) can initiate and promote the development of NMSC, the reasons why some individuals develop skin cancer and survival of keratinocytes at the cost of replicative potential, i.e. keratinocytes become senescent. Absence of IGF-1 receptor activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate, an inappropriate UVB response. In vivo, we have demonstrated that keratinocytes in young skin respond appropriately to UVB exposure; however, a surprisingly high percentage of keratinocytes in geriatric skin respond inappropriately to UVB irradiation. We hypothesize that this inappropriate response to UVB irradiation in geriatric skin could lead to initiated carcinogenic keratinocytes. Furthermore, the inappropriate UVB response in geriatric keratinocytes is due to the silencing of IGF-1 expression (and corresponding inactivation of the IGF-1 receptor) in geriatric skin. Finally, we have shown that treatment of geriatric skin with ablative dermal rejuvenation therapies can re- establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on sun-protected skin. In this proposal, we will expand our studies linking the susceptibility of geriatric skin to UVB-induced cancer to the IGF-1/IGF-1R signaling pathway. Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and advancing age. In fact, the majority of skin cancers are found in people over the age of 60; therefore, age is also a risk factor for the development of skin cancer. Using data derived from recent in vitro, in vivo, and epidemiological data, we have demonstrated that aberrations in insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling in geriatric skin contributes to their enhanced susceptibility to develop NMSC. In vitro, activation of the IGF-1 receptor regulates the response of normal human keratinocytes to UVB irradiation others do not are not fully understood. The IGF-1 receptor-dependent UVB response results in enhanced In the First, we will determine whether dermal rejuvenation therapies on geriatric skin will increase IGF-1 levels and correct the inappropriate UVB response for extended periods of time. Second, using human skin grafted onto immunodeficient mice we will mechanistically link the IGF-1 receptor-dependent inappropriate response to increased development of actinic neoplasia. Finally, mechanistic studies will examine elements of the IGF-1R signaling pathway in keratinocytes using UVB- irradiated human skin in vitro and in vivo. The successful completion of these specific aims will provide a direct link between the inappropriate UVB response in geriatric skin and the development of NMSC in geriatric patients. Furthermore, we will continue to evaluate the utility of prophylactic therapies that can prevent the occurrence of aging-associated photocarcinogenesis.

描述（由申请人提供）：非黑色素瘤皮肤癌 (NMSC) 在美国所有癌症中发病率最高。虽然 NMSC 的治疗很少致命，但据估计每年要花费我们的医疗系统超过 10 亿美元。因此，预防而不是切除 NMSC 有可能对医疗费用产生重大影响。虽然很明显，暴露于阳光中的紫外线成分（特别是 UVB）可以引发和促进 NMSC 的发展，但一些人患上皮肤癌和角质形成细胞存活的原因是以复制潜力为代价的，即角质形成细胞衰老。如果没有 IGF-1 受体激活，角质形成细胞对 UVB 诱导的细胞凋亡更加敏感，但存活下来的角质形成细胞仍保留增殖能力，这是一种不适当的 UVB 反应。在体内，我们已经证明年轻皮肤的角质形成细胞对 UVB 照射有适当的反应；然而，老年皮肤中角质形成细胞对 UVB 照射的反应异常高，比例高得惊人。我们推测，老年皮肤对 UVB 照射的这种不适当反应可能会导致致癌角质形成细胞的产生。此外，老年角质形成细胞中不适当的 UVB 反应是由于老年皮肤中 IGF-1 表达的沉默（以及相应的 IGF-1 受体的失活）所致。最后，我们已经证明，采用剥脱性真皮再生疗法治疗老年皮肤可以重新建立年轻的 IGF-1 水平，并随后恢复防晒皮肤上适当的 UVB 反应。在本提案中，我们将扩展我们的研究，将老年皮肤对 UVB 诱发的癌症的易感性与 IGF-1/IGF-1R 信号通路联系起来。尽管皮肤癌可以发生在任何年龄，但皮肤癌的发生与年龄增长之间存在很强的相关性。事实上，大多数皮肤癌发生在 60 岁以上的人群中；因此，年龄也是发生皮肤癌的危险因素。利用最近的体外、体内和流行病学数据，我们证明老年皮肤中胰岛素样生长因子-1 (IGF-1)/IGF-1 受体信号传导的异常导致其发生 NMSC 的易感性增强。在体外，IGF-1 受体的激活调节正常人角质形成细胞对 UVB 照射的反应，但其他方面尚未完全了解。 IGF-1 受体依赖性 UVB 反应导致增强首先，我们将确定老年皮肤的真皮再生疗法是否会增加 IGF-1 水平并在较长时间内纠正不适当的 UVB 反应。其次，使用移植到免疫缺陷小鼠身上的人类皮肤，我们将在机制上将 IGF-1 受体依赖性不适当反应与光化性肿瘤的发展增加联系起来。最后，机制研究将使用 UVB 照射的人体皮肤在体外和体内检查角质形成细胞中 IGF-1R 信号通路的元件。这些具体目标的成功完成将为老年皮肤中不适当的 UVB 反应与老年患者 NMSC 的发展之间提供直接联系。此外，我们将继续评估预防性疗法的效用，以预防与衰老相关的光致癌的发生。