ALCOHOL AND NATURAL KILLER CELL ACTIVITY

酒精和自然杀伤细胞活性

• 批准号: 3069362
• 负责人: GARY G MEADOWS
• 金额: $ 7.75万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3069362
• 关键词: B lymphocyte; T lymphocyte; alcoholic beverage consumption; athymic mouse; bone marrow; cell mediated cytotoxicity; cell mediated lymphocytolysis test; cell population study; cell sorting; chemical carcinogenesis; chemical related neoplasm /cancer; corticosterone; cytolysis; ethanol; immunosuppression; interferons; interleukin 1; interleukin 2; laboratory mouse; macrophage; metastasis; natural killer cells; neoplasm /cancer immunology; prostaglandin E; spleen

This is a request for an ADAMHA SDA, Level II award. The long-term career goal is to integrate immunology and alcohol research to study the effect of ethanol as an immune modulator of carcinogenesis, cancer growth, and metastasis. Specifically, the applicant will broaden his technological expertise in cell-mediated immunity and conduct experiments to define the mechanisms of ethanol's immunomodulation of natural killer (NK) cell activity at the biochemical and molecular levels. This award will facilitate the implementation of human research involving the role of alcohol as an immune modulator, and determine the biological relevance of alcohol-related immunosuppression to cancer. Currently, the applicant's research efforts are hampered by a high teaching load and substantial service responsibilities. If the SDA is funded, teaching responsibilities will be decreased from 25% to 0%, service responsibilities from 15% to 1%, and administrative responsibilities from 15% to 9%. Concurrent with these reductions will be an increase in research effort from 40% to 85%. The additional time for research will enable the applicant to visit other immunology laboratories and to import new biochemical and molecular techniques into his own research program. The hypothesis of the research proposal is that the suppressive effects of alcohol on NK cells are due to a combination of changes in the proportion of NK cells to other lymphocytes and decreased responsiveness of the NK cell. To examine this hypothesis, NK cell activity and distribution within the body will be determined after short-term and long-term ethanol consumption. Splenic NK cell activity will be compared with activity from other body compartments. The proportion and total number of NK cells relative to B lymphocytes, T lymphocytes, and macrophages will be assessed by flow cytometry. If distribution is affected, then the hypothesis that stress induced by ethanol consumption and/or decreased interferon (IFN) production contributes to these effects will be tested. Both factors modulate lymphocyte recruitment and distribution. The award will enhance the applicant's ability to examine the mechanisms underlying the suppressive effects of ethanol on NK cell activity. Possible defects in production of NK cytotoxic factors, alteration of target specificity, and altered binding or internalization of IL2 will be examined. If initial studies suggest that NK cell activity is modulated by the presence of other lymphocytes and macrophages, then controlled mixing experiments will be conducted using spleen cell suspensions purified for macrophages, B lymphocytes, T lymphocytes, and highly enriched NK cells. Enhanced production of suppressive factors such as PGE2 or reduced production of stimulatory factors, such as ILl, IL2, and/or TFN, will be examined if mixing experiments indicate a role for one or more of these cells in modulation of NK cell activity. The additional expertise obtained in molecular biology will enable the applicant ultimately to evaluate ethanol's effect on immunomodulators at the molecular level.

这是Adamha SDA，第二级奖的请求。 这 长期职业目标是将免疫学和酒精研究整合到 研究乙醇作为癌变的免疫调节剂的作用， 癌症生长和转移。 具体而言，申请人将扩大 他在细胞介导的免疫和行为方面的技术专业知识 定义乙醇免疫调节机制的实验 天然杀伤（NK）细胞活性在生化和分子上 水平。 该奖项将有助于实施人类研究 涉及酒精作为免疫调节剂的作用，并确定 酒精相关免疫抑制与癌症的生物学相关性。 目前，申请人的研究工作受到高度障碍 教负载和实质性服务责任。 如果SDA是 资助，教学责任将从25％降至0％， 服务职责从15％到1％，行政管理 责任从15％到9％。 与这些减少的同时发生 将研究工作从40％增加到85％。 额外的时间 对于研究，将使申请人访问其他免疫学 实验室并将新的生化和分子技术导入到 他自己的研究计划。 研究建议的假设是 酒精对NK细胞的抑制作用是由于 NK细胞比例与其他淋巴细胞的变化的结合 并降低了NK细胞的响应能力。 为了审查这一假设， NK细胞活性和体内的分布将确定 短期和长期乙醇消耗后。 脾脏NK细胞 活动将与其他身体隔室的活动进行比较。 NK细胞相对于B淋巴细胞的比例和总数 淋巴细胞和巨噬细胞将通过流式细胞仪进行评估。 如果 分布受到影响，然后是由 乙醇消耗和/或减少干扰素（IFN）生产 有助于这些效果。 这两个因素都调节 淋巴细胞募集和分布。 该奖项将增强 申请人检查抑制性机制的能力 乙醇对NK细胞活性的影响。 生产中可能的缺陷 NK细胞毒性因素，目标特异性的改变和改变 将检查IL2的结合或内在化。 如果最初的研究 表明NK细胞活性是通过其他其他 淋巴细胞和巨噬细胞，然后受控的混合实验将是 使用用于巨噬细胞纯化的脾细胞悬浮液进行的 淋巴细胞，T淋巴细胞和高度富集的NK细胞。 增强 产生抑制因素，例如PGE2或减少的生产 如果刺激因素，例如生病，IL2和/或TFN，如果 混合实验表明其中一个或多个在 NK细胞活性的调节。 获得的其他专业知识 分子生物学将使申请人最终能够评估 乙醇对分子水平的免疫调节剂的影响。