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

基本信息

批准号：
8321070
负责人：
GARY G MEADOWS
金额：
$ 21.88万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321070
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 Fostering Grant Granzyme Hypoglycemia Immune Immune response Immunity Incidence Interferon Type II Interferons Interleukin-2 Intravenous Knock-out Knockout Mice Lung Lymphocyte Lymphokines Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mentors Metastatic Melanoma Metastatic Neoplasm to the Lung Modeling Mus Natural Killer Cells Neoplasm Metastasis Nude Mice Organ Oxidative Stress Patients Play Population Production 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

项目摘要

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）：本次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，以培养 5 名研究兴趣集中在酒精研究的初级研究员的职业生涯。提供了一个具体的指导计划，并通过一些机构资源进行了补充。该奖项还将允许候选人开展和扩大他对酒精在癌症进展中的作用的研究，提高人们对酒精作为癌症危险因素的认识，并在这些领域开发合作机会。酗酒是一个世界性问题，与各种癌症发病率增加有关；然而，其在癌症进展中的作用尚不清楚。该研究计划针对癌症进展，并基于长期饮酒可减少小鼠黑色素瘤转移的初步数据。由自然杀伤 (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，饮酒显着增加产生 IFN-g 的 NKT 和 T 记忆细胞。即使转移受到抑制，饮酒的小鼠也会过早死亡，并且将研究与这种存活率下降相关的机制。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-g 增加所致。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综合作用来降低存活率。为了检验这些假设，我们提出以下具体目标： 1. 确定 NKT 细胞和 T 细胞对饮酒抑制黑色素瘤转移机制的贡献 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、携带黑色素瘤的小鼠存活率降低相关的机制。将饮用水中的 20% w/v 酒精给予雌性 C57BL/6、NKT 敲除小鼠、IFN-g 敲除小鼠和裸鼠，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癌和肺癌转移的影响。流式细胞术和 ELISA 测定将用于确定淋巴细胞群体、表面和细胞内标记物表达、细胞因子产生细胞和细胞因子浓度。