Prevention of UVB-induced skin cancer using sulforaphane: roles of AP-1 and Nrf2.

使用萝卜硫素预防 UVB 诱发的皮肤癌：AP-1 和 Nrf2 的作用。

• 批准号: 7920527
• 负责人: Sally E Dickinson
• 金额: $ 9.52万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920527
• 关键词: Accounting; Actinic keratosis; Acute; Affect; American Association of Cancer Research; Animals; Arizona; Bioethics; Biological Markers; Biometry; Cancer Biology; Cancer Center; Cancer Model; Cell Nucleus; Cells; Chemicals; Chemopreventive Agent; Chromatin; Chronic; Clinical Research; Clinical Trials; Cream; Cysteine; DNA Binding; DNA Binding Domain; DNA Damage; Data; Development Plans; Dose; Double-Blind Method; Drug Formulations; Epidermis; Exposure to; Family member; Forearm; Genotype; Goals; Histopathology; Human; Incidence; Institutes; Isothiocyanates; K-Series Research Career Programs; Knock-out; Knockout Mice; Light; Link; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Measurement; Mentors; Methodology; Modeling; Molecular; Mus; Mutate; Mutation; NQO1 gene; Nuclear; Oxidants; Oxidation-Reduction; Patients; Phase; Phenotype; Placebo Control; Placebos; Prevention; Prevention program; Program Research Project Grants; Proliferation Marker; Proteins; Punch Biopsy; Randomized; Reference Standards; Regulation; Relative (related person); Research Personnel; Risk; Role; Safety; Sampling; Scientist; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Staining method; Stains; Statistical Distributions; Sulforaphane; Testing; The Sun; Toxic effect; Training; Transactivation; Transcription Factor AP-1; Transgenic Mice; Tumor Burden; UVB induced; Ultraviolet B Radiation; Work; activating transcription factor; anticancer research; cancer chemoprevention; cancer diagnosis; cancer prevention; carcinogenesis; career development; cruciferous vegetable; interest; keratinocyte; meetings; mutant; oxidative damage; planetary Atmosphere; prevent; programs; response; safety study; safety testing; skin cancer prevention; stem; symposium; tool; transcription factor; treatment duration; tumor; volunteer

Non-melanoma skin cancer (NMSC) rates are rising due to factors such as increased UVB light penetrating our atmosphere. Skin cancer, the majority of which is NMSC, accounts for nearly 40% of all diagnosed cancers in the U.S. It is my goal as a scientist to find new, applicable and affordable topical compounds which will be used to reduce the incidence of NMSC in humans. A K07 Career Development Award (CDA) is the most effective means for me to begin to accomplish these objectives and become a productive top-level cancer biologist. To accomplish this goal, I must become well-trained in cancer biology and clinical trial methodology. As part of my career development plan, I have assembled a team of outstanding mentors in skin cancer research, mouse studies, drug formulation, and clinical trials. I will have regular interactions with my mentors and will receive didactic training in subjects such as clinical trial management, bioethics, and biostatistics. I will attend AACR conferences, meetings for the Skin Cancer Program Project Grant and seminars in Cancer Prevention and Control. The Arizona Cancer Center and the Skin Cancer Institute provide me with unique and valuable tools for furthering my training and accomplishing my goals. Scientifically, this CDA will help me to examine the roles of AP-1 and Nrf2 in the mechanism of action of the chemopreventive compound sulforaphane (SF) in UVB-treated skin. SF is an isothiocyanate found in cruciferous vegetables, and inhibits carcinogenesis in several models, possibly due to .induction of the transcription factor Nf E2-related factor 2 (Nrf2). Additionally, SF blocks the activity and DNA-binding ability of the activator protein-i (AP-1) transcription factor, a key component in UVB-induced.skin carcinogenesis. We hypothesize that SF. inhibits DVB-induced skin carcinogenesis and will reduce the,risk of squarnous cell carcinogenesis in patients with sun-damaged skin through a dual mechanism of action: Nrf2 activation leading to reduced pxidative DNA damage, and AP-1 inhibition through direct redox modulation. To.test this hypothesis we will .1)test whether the inhibitory effect of SF on AP-1 transactivation and skin carcinogenesis is due.to.chemical interactions with the DNA binding domain of cFos and/or cJun; 2):test thejnfluence of SF- induced Nrf2 on-protection against acute UVB-induced mouse skin damage and chronic UVB-induced NMSC; ,3)test the safety and efficacy of topical purified SF in humans (a Phase,l/lla clinical.trial)..,

由于UVB透光率增加等因素，非黑色素瘤皮肤癌(NMSC)的发病率正在上升 我们的大气。皮肤癌，其中大部分是NMSC，占所有诊断的近40% 美国的癌症。作为一名科学家，我的目标是找到新的、适用的和负担得起的局部化合物 它将被用来减少人类NMSC的发生率。K07职业发展奖(CDA)是 对我来说，开始实现这些目标并成为富有成效的最高层的最有效手段 癌症生物学家。为了实现这一目标，我必须在癌症生物学和临床试验方面接受良好的培训。 方法论。作为我职业发展计划的一部分，我组建了一支优秀的导师团队 皮肤癌研究、小鼠研究、药物配方和临床试验。我会定期与之互动 我的导师将接受临床试验管理、生物伦理学和 生物统计学。我将参加AACR会议，皮肤癌计划项目赠款和 癌症预防与控制研讨会。亚利桑那州癌症中心和皮肤癌研究所 为我提供独特和有价值的工具来进一步培训和实现我的目标。 科学地讲，这篇CDA将帮助我研究AP-1和NRF2在糖尿病的作用机制中的作用。 化学预防化合物萝卜硫素(SF)在UVB治疗的皮肤中的应用。SF是一种异硫氰酸酯 十字花科蔬菜，并在几个模型中抑制致癌，可能是由于诱导 转录因子NFE2相关因子(NRF2)。此外，SF还阻断了DNA结合活性和DNA结合能力 激活蛋白-1(AP-1)转录因子，是UVB诱导的皮肤癌的关键成分。 我们假设科幻小说。抑制DVB诱导的皮肤癌变，并将降低方形细胞的风险 日晒损伤皮肤患者通过双重作用机制致癌：Nrf2激活 从而减少DNA氧化损伤，并通过直接氧化还原调节抑制AP-1。来测试一下这个 假设我们将1)测试SF对AP-1反式激活和皮肤癌的抑制作用 与CFos和/或cJun的DNA结合域的化学作用；2)：测试SF- 诱导的NRF2对UVB急性和慢性皮肤损伤的保护作用 NMSC；，3)局部纯化SF对人体的安全性和有效性测试(A期，L/11a临床试验)，