Inhibition of UVB-induced inflammation and carcinogenesis by black raspberry extr

描述（由申请人提供）：与一般人群相比，移植受者发生非黑色素瘤皮肤癌的风险更大，特别是侵袭性、危及生命的鳞状细胞癌。除了紫外线（UV）暴露外，多种抗排斥药物的免疫抑制也与皮肤癌风险增加有关。理想情况下，这种治疗可以在日光暴露的损害发生后施用，不会以药丸或片剂形式施用，并且具有有限的全身作用。我们假设，黑树莓提取物（BRE）的局部应用符合这些标准，应探索作为非黑色素瘤皮肤癌的治疗/预防。我们的初步数据表明，局部BRE应用后，UVB暴露减少DVB诱导的炎症和抑制肿瘤的发展。这项提案将寻求确定炎症减少的机制。该提案使用鼠模型来测试BRE抑制UV诱导的皮肤炎症并通过抗氧化特性抑制肿瘤形成的新假设，导致角质形成细胞活化、增殖和DNA损伤减少，中性粒细胞浸润和活性减少，以及CD 4 + T细胞浸润增加（具体目标1）。此外，我们假设，当在肿瘤形成后给药时，BRE将减缓肿瘤向侵袭性SCC的进展（具体目标2）。我们的研究人员团队能够独特地测试假设并进行这些实验，这是由于在移植和细胞免疫学（VanBuskirk），光致癌和病理学（Kusewitt），皮肤炎症和致癌（Oberyszyn）以及使用黑树莓提取物预防和治疗癌症（Stoner和Hecht）方面的互补专业知识。从我们在该临床前模型中的研究中获得的数据将提供对BRE抑制炎症和肿瘤形成的机制的见解，并将为R 01应用中更完整的机制解剖和利用提供初步数据。这些研究与RFA和NCCAM的使命直接相关，因为它们开始剖析局部应用天然产品BRE减少日光暴露后炎症从而抑制皮肤肿瘤形成的机制。这些研究还将确定BRE是否会减缓肿瘤进展，这对未来的临床应用非常重要

DESCRIPTION (provided by applicant): Compared to the general population, transplant recipients are at greater risk for developing non-melanoma skin cancers, especially aggressive, life-threatening squamous cell carcinomas. In addition to ultraviolet light (UV) exposure, immunosuppression from multiple anti-rejection medications is implicated in the increased risk of skin cancer There is a clear need for treatments to prevent and treat skin cancer in transplant recipients. Ideally, such treatments could be administered after the damage of sun exposure has occurred, would not be administered as a pill or tablet and would have limited systemic effects. We hypothesize that topical application of black raspberry extracts (BRE) fulfill these criteria and should be explored as a treat- ment/preventive for non-melanoma skin cancer. Our preliminary data indicate that topical BRE applied after UVB exposure reduce DVB-induced inflammation and inhibit tumor development. This proposal will seek to determine the mechanisms by which inflammation is reduced. This proposal uses a murine model to test the novel hypothesis that BRE inhibit UV-induced skin inflammation and inhibit tumor formation through anti- oxidant properties, resulting in reduced keratinocyte activation, proliferation and DNA damage, reduced neutrophil infiltration and activity, and increased CD4+ T cell infiltration (Specific Aim 1). Further, we hypothesize that BRE will slow tumor progression to aggressive SCC when administered after tumors have formed (Specific Aim 2). Our team of investigators is uniquely able to test the hypothesis and perform these experiments due to complementary expertise in transplant and cellular immunology (VanBuskirk), photo- carcinogenesis and pathology (Kusewitt), skin inflammation and carcinogenesis (Oberyszyn), and the use of black raspberry extracts to prevent and treat cancer (Stoner and Hecht). The data obtained from our studies in this pre-clinical model will provide insights into the mechanisms by which BRE inhibit inflammation and tumor formation and will provide preliminary data for a more complete mechanism dissection and utilization in an R01 application. These studies are directly relevant to the RFA and the mission of NCCAM in that they begin dissection of the mechanisms by which topical application of a natural product, BRE, reduce inflammation after sun exposure and thereby inhibit skin tumor formation. These studies will also determine if BRE slow tumor progression, which will be important for future clinical applications