Chemoprotective role of silver nanoparticles in UV radiation-induced skin carcino

描述（由申请人提供）：每年，皮肤癌的新发病例比乳腺癌、前列腺癌、肺癌和结肠癌的合并发病率还要多，这清楚地强调了制定有效预防策略的必要性。来自太阳的紫外线（UV）辐射，特别是其UVB成分，是皮肤癌的最确定的流行病学原因。UVB辐射导致DNA损伤，如果不修复，最终导致致癌突变的积累和随后的恶性转化。目前，几种局部防晒制剂被用于防止紫外线辐射引起的皮肤损伤和致癌作用;然而，似乎没有一种是非常有效的，皮肤癌的发病率每年都在继续上升。该提议基于我们的新发现，其证明了用银纳米颗粒（AgNP）预处理人永生化角质形成细胞（HaCaT）：i）在暴露于UVB辐射时导致环丁烷嘧啶二聚体（CPD）的形成减少，ii）保护HaCaT角质形成细胞免于UVB辐射诱导的细胞凋亡，iii）抑制基础以及UVB诱导的ROS产生，和iv）诱导细胞周期停滞在G1/S期。基于这些有希望的发现，我们假设银纳米粒子（AgNPs）是有效的化学预防剂对UVB诱导的皮肤损伤和致癌作用。该试点提案的总体目标是使用生物化学和功能测定产生更多支持这一假设的数据，这将为设计严格的研究以探索银纳米颗粒的化学预防潜力提供强有力的支持。因此，我们提出了两个互补的具体目标：1）定义的化学保护作用的银纳米粒子对UVB辐射诱导的皮肤癌发生的分子机制，和2）评估的化学保护功效的银纳米粒子对UVB诱导的皮肤癌发生在小鼠模型。目标1中提出的研究将为我们提供AgNPs对UVB诱导的皮肤癌发生的化学保护作用的机理洞察，而目标2中提出的研究将为AgNPs的化学保护功效提供直接的临床前证据。从拟议的试点研究的结果将形成未来的调查，以开发基于银纳米粒子的有效的化学预防制剂的基础。

DESCRIPTION (provided by applicant): Each year, there are more new cases of skin cancer than the combined incidence of breast, prostate, lung and colon cancers, which clearly emphasizes the need for the development of effective prevention strategies. Ultraviolet (UV) radiation from sun, particularly its UVB component, is the most established epidemiological cause of skin cancer. UVB radiation causes DNA damage, which if remained unrepaired ultimately leads to accumulation of carcinogenic mutations and subsequent malignant transformation. Currently, several topical sunscreen formulations are being used for protection against UV radiation-induced skin injury and carcinogenesis; however, none seem to be very much effective and incidence of skin cancer continues to rise every coming year. This proposal is based on our novel findings demonstrating that the pretreatment of human immortalized keratinocytes (HaCaT) with silver nanoparticles (AgNPs): i) leads to reduced formation of cyclobutane pyrimidine dimers (CPDs) upon exposure to UVB radiation, ii) protects the HaCaT keratinocytes from UVB radiation-induced apoptosis, iii) suppresses basal as well as UVB-induced ROS production, and iv) induces cell cycle arrest in G1/S phase. Based on these promising findings, we hypothesize that Silver nanoparticles (AgNPs) are effective chemopreventive agents against UVB-induced skin injury and carcinogenesis. The overall objective of this pilot proposal is to generate additional supportive data towards this hypothesis using biochemical and functional assays, which would provide strong support for the design of rigorous studies to explore the chemopreventive potential of AgNPs. Thus, we propose two complementary Specific Aims: 1) Define the molecular mechanisms underlying chemoprotective effects of silver nanoparticles against UVB radiation-induced skin carcinogenesis, and 2) Evaluate the chemoprotective efficacy of silver nanoparticles against UVB-induced skin carcinogenesis in mouse model. Studies proposed in Aim 1 will provide us mechanistic insight into the chemoprotective action of AgNPs against UVB-induced skin carcinogenesis, while those proposed in Aim 2 will provide direct pre-clinical evidence for chemoprotective efficacy of AgNPs. The outcome from the proposed pilot studies will form the bases for future investigations to develop AgNPs-based effective chemopreventive formulation(s).