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: 6628448
• 负责人: HUACHEN WEI
• 金额: $ 28.65万
• 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/6628448
• 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：（申请人的描述）本申请建议测试 假设金雀异黄酮（一种大豆异黄酮）可抑制紫外线辐射 (UVR) 诱导嘧啶二聚体和氧化 DNA 损伤，并调节 UVR 激活信号转导级联，从而抑制起始和 促进光致癌作用。该项目的首要目标是确定 如果在使用金雀异黄素之前或之后可以预防紫外线引起的皮肤 致癌作用。金雀异黄酮将在无毛小鼠身上局部施用 暴露于紫外线。保护效果将通过分析来评估 潜伏期、肿瘤发生率和多重性。第二个目标是评估 金雀异黄素对启动、促进和进展的影响 UVR 诱发皮肤癌。金雀异黄素将局部应用于小鼠 在开始使用 UVR 剂量之前对皮肤进行测试，然后进行 TPA 促进或应用 在 DMBA 引发小鼠皮肤的紫外线照射之前。 UVR-化学组合 模型将用于剖析反启动或反促进效应 金雀异黄素对 UVR 暴露的影响。抗进展效果将通过以下方式评估 将金雀异黄素应用于现有的皮肤肿瘤并记录肿瘤 回归率和恶变率。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 和促销，例如DNA 光产物、DNA 氧化损伤、炎症 反应、鸟氨酸脱羧酶 (ODC) 诱导和原癌基因表达 体内。第四个目标是进一步阐明分子机制 由此金雀异黄素在体外抑制光致癌作用。的效果 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，表皮生长因子受体的磷酸化 以及小鼠和人类中 AP-1 转录因子的激活 将检查角质形成细胞。最后，申请人将评估 金雀异黄酮在保护紫外线引起的红斑和不适方面的功效 人类受试者的皮肤。此外，某些分子终点，例如 8-OHdG、嘧啶二聚体、p53 和增殖细胞核抗原 (PCNA) 将在人类皮肤活检和重组中检测到表达 3 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 对抗人类皮肤癌和光损伤的治疗剂。