Mechanisms of Oral Cancer Inhibition by Bioactive Phytochemicals in Black Raspberries

项目摘要/摘要 这项提议将促进应聘者的研究和职业发展培训，以实现其目标 成为一名在口腔癌免疫学和口腔癌免疫方面具有专业知识的知名独立调查员 化学预防。仅在美国，预计将有48330例新病例和9570例 2016年的死亡人数。值得注意的是，在非洲人中，口腔癌的死亡率高得不成比例。 美国男性。因此，新的、有效的口腔癌防治策略迫在眉睫 需要的。最近的临床和临床前研究表明，黑树莓(BRBs)具有显著的能力 抑制口腔肿瘤的形成。然而，关于哪种生物活性化合物的知识仍然有限。 在抑制口腔癌方面，BRB是最重要的，以及它们如何影响不同的细胞和分子 构成口腔肿瘤的微环境。这些知识对于推动……的发展至关重要。 BRB植物化学物质在口腔癌防治中的应用。此K01应用程序的目标是确定 生物活性BRB植物化学物质抑制口腔癌的机制 口腔肿瘤微环境中促进癌变的基本成分：(I)髓系 衍生抑制细胞(MDSC)和(II)促炎症细胞因子--巨噬细胞移动抑制因子 (MIF)。我们假设BRBs中的植物化学物质通过预防MDSC来抑制口腔癌的发生 募集/活性以及抑制MIF信号通路，这些特性可以在口服中利用 癌症干预。在具体目标1中提出的研究将确定BRB植物化学物质对 MDSC在口腔癌中的作用。在具体目标2中提出的研究将确定BRB的影响 口腔癌过程中植物化学物质对MIF相关信号的影响。最后，在具体目标3中拟议的研究将 确定BRB植物化学物质与口腔癌预防和治疗相结合的效果 治疗。这些研究将扩大我们对BRB植物化学物质抑制口腔癌的理解 推进BRB植物化学制剂作为口腔癌辅助治疗策略的应用。 为了实现这些研究目标并促进他向研究独立的过渡，候选人将 丰富他在以下方面的培训和专业知识：(I)代谢组学；(Ii)生物统计学；(Iii)癌症临床试验。这将是 通过与经验丰富且尽职尽责的导师团队、正式的教学和 实践培训，以及研究教育和培训计划。拟议的培训和研究 活动将帮助候选人转变为一名成熟的、富有成效的独立调查员， 一项专注于利用生物活性植物化学物质的免疫调节特性的研究计划 改善癌症预防和治疗结果。

PROJECT SUMMARY/ABSTRACT This proposal will facilitate the research and career development training of the candidate in his goal to become an established independent investigator with expertise in oral cancer immunology and chemoprevention. In the United States alone, it is expected that there will be 48,330 new cases and 9,570 deaths in 2016. Significantly, there is a disproportionately high mortality rate of oral cancer among African- American males. Therefore, new and effective oral cancer prevention and treatment strategies are desperately needed. Recent clinical and preclinical studies demonstrate the remarkable ability of black raspberries (BRBs) to inhibit tumor formation in the oral cavity. Yet, there is still limited knowledge on which bioactive compounds in BRBs are most important in inhibiting oral cancer, and how they affect the different cells and molecules that make up the oral tumor microenvironment. This knowledge is essential in order to advance the development of BRB phytochemicals in oral cancer prevention and treatment. The goal of this K01 application is to determine the mechanisms underlying oral cancer inhibition by bioactive BRB phytochemicals, with a focus on two essential components of the oral tumor microenvironment known to promote carcinogenesis: (i) myeloid derived suppressor cells (MDSC) and (ii) the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF). We hypothesize that phytochemicals in BRBs inhibit oral carcinogenesis by preventing MDSC recruitment/activity as well as suppressing MIF signaling pathways, properties which can be exploited in oral cancer intervention. Studies proposed in Specific Aim 1 will determine the impact of BRB phytochemicals on MDSC function during oral cancer. Studies proposed in Specific Aim 2 will determine the effects of BRB phytochemicals on MIF-associated signaling during oral cancer. Finally, proposed studies in Specific Aim 3 will determine the efficacy of combinatorial approaches with BRB phytochemicals for oral cancer prevention and treatment. These studies will expand our understanding of oral cancer inhibition by BRB phytochemicals and advance the application of BRB phytochemicals as complementary therapeutic strategies against oral cancer. To accomplish these research goals and facilitate his transition to research independence, the candidate will enrich his training and expertise in: (i) metabolomics; (ii) biostatistics; and (iii) cancer clinical trials. This will be accomplished through interaction with an experienced and committed team of mentors, formal didactic and hands-on training, and research education and training programs. The proposed training and research activities will assist in the candidate’s transition to an established and productive independent investigator with a research program focused on exploiting the immunomodulatory properties of bioactive phytochemicals to improve cancer prevention and treatment outcomes.