Mechanistic efforts of chronic alcohol on tumor metastasis and survival

慢性酒精对肿瘤转移和生存的机制作用

• 批准号: 7918767
• 负责人: GARY G MEADOWS
• 金额: $ 21.57万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918767
• 关键词: Ablation; Address; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Area; Award; Awareness; Biological; Biological Assay; Body fat; Cancer Patient; Cause of Death; Cell Survival; Cells; Cessation of life; Chronic; Cutaneous Melanoma; Data; Ear; Endocrine; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Animal Model; Female; Figs - dietary; Fostering; Grant; Granzyme; Hypoglycemia; Immune; Immune response; Immunity; Immunologic Factors; Incidence; Interferon Type II; Interleukin-2; Intravenous; Knock-out; Knockout Mice; Lung; Lymphocyte; Lymphokines; Malignant Neoplasms; Malignant neoplasm of lung; Mentors; Metastatic Melanoma; Metastatic Neoplasm to the Lung; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Nude Mice; Organ; Oxidative Stress; Patients; Play; Population; Production; Prostate; Research; Research Personnel; Resources; Risk Factors; Role; Senior Scientist Award; Skin Cancer; Source; Staging; Surface; T memory cell; T-Lymphocyte; Testing; Time; Wages; alcohol effect; alcohol research; base; career; chronic alcohol ingestion; cytokine; drinking water; effective therapy; external ear auricle; interest; melanoma; perforin; problem drinker; text searching; tumor; tumor progression

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.

描述（由申请人提供）：该高级科学家奖励申请将为候选人提供部分工资支持和释放时间，以培养5名研究人员的研究兴趣，他们的研究兴趣着重于酒精研究。提供了一项特定的指导计划，该计划由几种机构资源增强。该奖项还将允许候选人对酒精在癌症进展中的作用，促进对酒精作为癌症的危险因素的认识并在这些领域发展协作机会的研究。酗酒是一个全球问题，与各种癌症的发病率增加有关；但是，其在癌症进展中的作用尚不清楚。该研究计划解决了癌症的进展，并基于初步数据，即长期饮酒可降低鼠类黑色素瘤的转移。天然杀手（NK）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至关重要。初步数据表明，饮酒会显着增加IFN-G产生NKT和T记忆细胞。即使抑制转移，饮酒小鼠也会过早地死亡，并且将研究生存率降低的机制。假设慢性酒精消耗的抗转移性作用是由于NKT和记忆T细胞增加了IFN-G的产生。进一步假设，通过对改变T细胞存活，低血糖和氧化应激的影响的结合，饮酒可以降低存活率。为了检验这些假设，我们提出了以下具体目的：1。确定NKT细胞和T细胞对饮酒抑制黑色素瘤转移2的机制的贡献。确定酒精对其他动物肿瘤模型转移的影响。 3。确定与饮酒，含黑色素瘤小鼠的生存率降低相关的机制。饮用水中的酒精为20％w/v，将用于雌性C57BL/6，NKT敲除，IFN-G基因敲除和裸鼠，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和肺癌转移的影响。流式细胞仪和ELISA分析将用于确定淋巴细胞群体，表面和细胞内标记，细胞因子产生细胞以及细胞因子浓度。