Cerebral Microcirculation During Alcohol Consumption

饮酒期间的大脑微循环

基本信息

批准号：
6915983
负责人：
WILLIAM G MAYHAN
金额：
$ 24.81万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chronic consumption of alcohol is a major contributing factor in the pathogenesis of hemorrhagic and ischemic stroke, and appears to contribute to cognitive impairment in animals and humans. While we have shown that chronic alcohol consumption impairs nitric oxide synthase (NOS)-dependent responses of cerebral arterioles, cellular/molecular mechanisms by which alcohol consumption contributes to cerebrovascular dysfunction remain unknown. The central theme of our application is to determine the mechanisms contributing to impaired NOS activity and reactivity of cerebral vessels during alcohol consumption. This central theme not only involves an examination of the role of co-factors of NOS, as possible targets of oxidative stress, but also involves cellular pathways responsible for the genesis of oxidative stress to affect the influence of nitric oxide on cerebrovascular reactivity. We propose the following aims: In Specific Aim #1, we will establish the activation mechanism and signaling cascade for NOS in cerebral arterioles during chronic alcohol consumption. We will test the hypothesis that chronic consumption of alcohol alters the role of nitric oxide in the regulation of basal tone and reactivity of cerebral arterioles. In Specific Aim #2, we will identify the role of NOS co-factors in impaired responses of cerebral arterioles during chronic consumption of alcohol. We will test the hypothesis that co-factors for NOS may influence reactivity of cerebral arterioles during chronic alcohol consumption. In Specific Aim #3, we will identify the role of cellular oxidant and antioxidant networks in impaired NOS-dependent reactivity of cerebral arterioles. We will test the hypothesis that activation of key cellular oxidative pathways by chronic consumption of alcohol contributes to impaired NOS-dependent reactivity of cerebral arterioles. In Specific Aim #4, we will establish a relationship between impaired cerebrovascular reactivity to brain morphology during chronic alcohol consumption. We will test the hypothesis that chronic alcohol consumption produces morphological alterations in cerebral vessels/brain tissue that may correlate with impaired cerebrovascular reactivity. In summary, we propose to utilize in vivo approaches coupled with new and innovative biochemical/molecular/-genetic/morphological approaches to identify cellular mechanisms contributing to impaired reactivity of cerebral arterioles during alcohol consumption. These studies will provide valuable new insights and will lead to new therapeutic approaches for the treatment of cerebrovascular abnormalities observed in chronic alcoholics.

描述（由申请人提供）：长期饮酒是出血性和缺血性中风发病机制的主要影响因素，并且似乎会导致动物和人类的认知障碍。虽然我们已经证明，长期饮酒会损害脑小动脉的一氧化氮合酶（NOS）依赖性反应，但饮酒导致脑血管功能障碍的细胞/分子机制仍不清楚。我们应用的中心主题是确定饮酒期间 NOS 活性和脑血管反应性受损的机制。这一中心主题不仅涉及对 NOS 辅助因子作为氧化应激可能靶标的作用的研究，还涉及负责氧化应激发生的细胞途径，从而影响一氧化氮对脑血管反应性的影响。我们提出以下目标：在具体目标#1中，我们将建立慢性饮酒期间脑小动脉NOS的激活机制和信号级联。我们将检验以下假设：长期饮酒会改变一氧化氮在调节脑小动脉基础张力和反应性中的作用。在具体目标#2 中，我们将确定 NOS 辅因子在长期饮酒期间脑小动脉反应受损中的作用。我们将检验以下假设：NOS 辅助因子可能会影响长期饮酒期间脑小动脉的反应性。在具体目标#3中，我们将确定细胞氧化剂和抗氧化网络在脑小动脉NOS依赖性反应性受损中的作用。我们将验证以下假设：长期饮酒激活关键细胞氧化途径会导致脑小动脉 NOS 依赖性反应性受损。在具体目标#4中，我们将建立长期饮酒期间脑血管反应受损与大脑形态之间的关系。我们将检验以下假设：长期饮酒会导致脑血管/脑组织形态发生改变，这可能与脑血管反应性受损有关。总之，我们建议利用体内方法与新的和创新的生化/分子/遗传/形态学方法相结合，以确定饮酒期间导致脑小动脉反应性受损的细胞机制。这些研究将提供有价值的新见解，并将带来治疗慢性酗酒者脑血管异常的新治疗方法。