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

描述（申请人提供）：每年皮肤癌的新发病例比乳腺癌、前列腺癌、肺癌和结肠癌的总发病率还要多，这明显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，特别是其中的中波紫外线（UVB）成分，是最确定的皮肤癌流行病学原因。UVB辐射导致DNA损伤，如果不进行修复，最终会导致致癌突变的积累和随后的恶性转化。目前，几种局部防晒配方被用于防止紫外线辐射引起的皮肤损伤和致癌；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。这一建议是基于我们的新发现，表明用银纳米颗粒（AgNPs）预处理人类永生化角质形成细胞（HaCaT）： 1)导致暴露于UVB辐射后环丁烷嘧啶二聚体（CPDs）的形成减少，2)保护HaCaT角质形成细胞免受UVB辐射诱导的凋亡，3)抑制基础以及UVB诱导的ROS产生，4)诱导细胞周期阻滞在G1/S期。基于这些有希望的发现，我们假设银纳米颗粒（AgNPs）是有效的化学预防剂，可预防uvb引起的皮肤损伤和致癌。该试点提案的总体目标是通过生化和功能分析为这一假设提供额外的支持数据，这将为设计严谨的研究来探索AgNPs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)明确银纳米粒子对UVB辐射诱发的皮肤癌变的化学保护作用的分子机制；2)在小鼠模型上评价银纳米粒子对UVB诱发的皮肤癌变的化学保护作用。在Aim 1中提出的研究将为我们提供AgNPs对uvb诱导的皮肤癌的化学保护作用的机制，而在Aim 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。拟议的试点研究的结果将构成未来研究的基础，以开发基于agnps的有效化学预防制剂。

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).