GENISTEIN IN INVESTIGATIVE AND CLINICAL DERMATOLOGY

金雀花素在皮肤病学研究和临床中的应用

• 批准号: 6945538
• 负责人: HUACHEN WEI
• 金额: $ 7.8万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-03 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945538
• 关键词: AP1 protein; antineoplastics; clinical research; dimethylbenzanthracene; enzyme induction /repression; epidermal growth factor; genistein; growth factor receptors; hairless mouse; high performance liquid chromatography; human subject; keratinocyte; mitogen activated protein kinase; northern blottings; ornithine decarboxylase; p53 gene /protein; phorbols; proliferating cell nuclear antigen; protooncogene; pyrimidine dimers; radiation carcinogenesis; radiation genetics; radioprotective agents; skin neoplasms; ultraviolet radiation

DESCRIPTION: (applicant's description) This application proposes to test the hypothesis that genistein, a soybean isoflavone, inhibits ultraviolet radiation {UVR)-induced pyrimidine dimers and oxidative DNA damage, and modulates UVR activated signal transduction cascades, thereby suppressing the initiation and promotion of photocarcinogenesis. The first aim of the project is to determine if pre- or post-application of genistein prevents UVR-induced skin carcinogenesis. Genistein will be topically applied to hairless mice during exposure to UVR. The protective efficacy will be evaluated by analyzing the latency period, tumor incidence and multiplicity. The second aim is to evaluate the effect of genistein on initiation, promotion, and progression of UVR-induced skin carcinogenesis. Genistein will be topically applied to mouse skin before an initiating dose of UVR, followed by TPA promotion, or applied before UV irradiation in DMBA initiated mouse skin. UVR-chemical combination models will be used to dissect the anti-initiation or anti-promotion effects of genistein on the UVR exposure. The anti-progression effect will be evaluated by applying genistein to existing cutaneous tumors and recording the tumor regression and malignant conversion rate. The third aim is to examine if genistein inhibits UVR-induced intermediate endpoints relevant to initiation and promotion, e.g. DNA photoproducts, oxidative DNA damage, inflammatory responses, ornithine decarboxylase (ODC) induction and protooncogene expression in vivo. The fourth aim is to further elucidate the molecular mechanism(s) whereby genistein inhibits photocarcinogenesis in vitro. The effect of genistein on UVR-induced activation of tyrosine protein/mitogen activated protein kinases, phosphorylation of the epidermal growth factor receptor as well as activation of the AP-1 transcription factor in murine and human keratinocytes will be examined. Lastly, the applicant will evaluate the efficacy of genistein in protection of UVR-induced erythema and discomfort in the skins of human subjects. In addition, certain molecular endpoints such as 8-OHdG, pyrimidine dimers, p53 and proliferating cell nuclear antigen (PCNA) expression will be detected in human skin biopsies and the reconstituted 3-dimensional human skin. Successful completion of the proposed studies will contribute to development of this soybean isoflavone as a preventive and/or therapeutic agent against human skin cancer and photodamage.

描述：(申请者描述)本申请拟测试 大豆异黄酮染料木素抑制紫外线辐射的假说 (UVR)诱导的嘧啶二聚体和DNA氧化损伤，并调节UVR 激活的信号转导级联，从而抑制启动和 促进光致癌。该项目的第一个目标是确定 金雀异黄素应用前后是否能阻止UVR诱导的皮肤 致癌。金雀异黄素将局部应用于无毛小鼠 暴露在紫外线辐射下。保护效果的评估将通过分析 潜伏期、肿瘤发生率和多发性。第二个目标是评估 金雀异黄素对卵巢癌细胞的启动、促进和进展的影响 紫外线诱导的皮肤癌。金雀异黄素局部应用于小鼠 在UVR启动剂量之前，然后进行TPA促进，或涂抹 紫外线照射前在DMBA溶液中启动小鼠皮肤。UVR-化学组合 模型将被用来剖析反启动或反促进的效果。 紫外线照射下的染料木素。将通过以下方法评估抗癌进展的效果 将染料木素应用于已有的皮肤肿瘤并记录肿瘤 消退率和恶转率。第三个目标是检查是否 金雀异黄素抑制UVR诱导的与起始相关的中间终点 和促进，例如DNA光产物，氧化DNA损伤，炎症性 应答、鸟氨酸脱羧酶(ODC)诱导和原癌基因表达 在活体内。第四个目的是进一步阐明分子机制(S) 染料木素在体外抑制光致癌作用。的影响 金雀异黄素对UVR诱导的酪氨酸蛋白/丝裂原活化的影响 蛋白激酶，表皮生长因子受体AS的磷酸化 以及AP-1转录因子在小鼠和人体内的激活 角质形成细胞将被检查。最后，申请者将评估 金雀异黄素对紫外线诱导的红斑和不适感的保护作用 人类研究对象的皮肤。此外，某些分子终点，如 8-OHdG、嘧啶二聚体、P53和增殖细胞核抗原 将在人类皮肤活检组织中检测到表达，并重组 三维人体皮肤。成功完成拟议的研究将 有助于开发这种大豆异黄酮作为预防和/或 针对人类皮肤癌和光损伤的治疗剂。