Mechanistic efforts of chronic alcohol on tumor metastasis and survival

该高级科学家奖申请将为候选人提供部分工资支持和释放时间，以促进5名研究兴趣集中在酒精研究的初级研究人员的职业生涯。提供了一个具体的辅导计划，并通过若干机构资源予以加强。该奖项还将允许候选人进行和扩大他对酒精在癌症进展中的作用的研究，以促进对酒精作为癌症风险因素的认识，并在这些领域发展合作机会。酒精滥用是一个世界性的问题，与各种癌症的发病率增加有关;然而，它在癌症进展中的作用还不清楚。该研究计划针对癌症进展，并基于长期饮酒会降低小鼠黑色素瘤转移的初步数据。由自然杀伤（NK）细胞和NKT细胞以及可能的记忆T细胞产生的干扰素γ（IFN-g）对于控制黑色素瘤的转移是必需的。初步数据表明，酒精消费显着增加IFN-g生产NKT和T记忆细胞。即使转移被抑制，饮酒小鼠也会过早死亡，并且将研究与这种存活率降低相关的机制。据推测，长期饮酒的抗转移作用是由于NKT和记忆T细胞产生的IFN-γ增加。进一步假设，饮酒通过改变T细胞存活、低血糖和氧化应激的组合效应降低存活率。为了验证这些假设，我们提出了以下具体目标：1。确定NKT细胞和T细胞对酒精消耗抑制黑色素瘤转移的机制的贡献2.确定酒精对其他动物肿瘤模型转移的影响。3.确定与饮酒、荷黑色素瘤小鼠存活率降低相关的机制。将给予雌性C57 BL/6、NKT敲除小鼠、IFN-g敲除小鼠和裸鼠饮用水中20% w/v的酒精，以评估与抑制黑色素瘤转移相关的机制。实验和自发转移测定也将用于检查酒精对前列腺癌和肺癌转移的影响。将使用流式细胞术和ELISA试验测定淋巴细胞群、表面和细胞内标志物表达、细胞因子产生细胞和细胞因子浓度。

DESCRIPTION (provided by applicant): This Senior Scientist Award application will provide partial salary support and release time for the candidate to foster the careers of 5 junior investigators whose research interests focus on alcohol research. A specific mentoring plan is provided that is augmented by several institutional resources. The award will also allow the candidate to conduct and expand his research on the role of alcohol in cancer progression, to promote awareness of alcohol as a risk factor for cancer, and to develop collaborative opportunities in these areas. Alcohol abuse is a worldwide problem and is associated with increased incidence of various cancers; however its role in cancer progression is not well understood. The research plan addresses cancer progression and is based on preliminary data that chronic alcohol consumption decreases metastasis of murine melanoma. Interferon gamma (IFN-g) produced by natural killer (NK) and NKT cells and possibly memory T cells is essential to control metastasis of melanoma. Preliminary data indicate that alcohol consumption significantly increases IFN-g producing NKT and T memory cells. Alcohol consuming mice die prematurely even though metastasis is inhibited and the mechanisms associated for this decrease in survival will be investigated. It is hypothesized that the antimetastatic effect of chronic alcohol consumption is due to increased production of IFN-g by NKT and memory T cells. It is further hypothesized that alcohol consumption decreases survival through a combination of effects on altering T cell survival, hypoglycemia, and oxidative stress. To test these hypotheses, we propose the following specific aims: 1. Determine the contributions of NKT cells and T cells to the mechanism by which alcohol consumption inhibits melanoma metastasis 2. Determine the effect of alcohol on metastasis of other animal tumor models. 3. Determine the mechanisms associated with decreased survival of alcohol consuming, melanoma-bearing mice. Alcohol, 20% w/v in the drinking water, will be given to female C57BL/6, NKT knockout, IFN-g knockout, and nude mice to assess the mechanisms associated with inhibition of melanoma metastasis. Experimental and spontaneous metastasis assays also will be used to examine the effects of alcohol on metastasis of prostate and lung cancer. Flow cytometric and ELISA assays will be used to determine lymphocyte populations, surface and intracellular marker expression, cytokine producing cells, and cytokine concentrations.