HEPATOCYTE VOLUME CONTROL AND ALCOHOLIC INJURY

这项提案的长期目标是阐明 慢性酒精摄入过程中肝细胞体积调节失败， 导致肝脏肿大。肝脏增大进而导致门脉 高血压、微循环障碍和缺氧性变性 肝功能。眼下的目标是确定慢性 小鼠摄入乙醇或急性给药乙醇 原代培养中的肝细胞会降低肝细胞的能力 来调节它们的音量。该项目将利用一部小说， 测量肝细胞水变化的电生理技术 音量。具体目标是：1)膜水的测定 肝细胞在原代培养中的通透系数以及 2)测定原代培养的肝细胞 单层培养调节其体积以响应对 外渗和容量调节是否会随着慢性疾病而减弱 和乙醇的急性影响；3)确定快速容量是否 培养肝细胞的调节促进二次主动转运 补偿累积有机渗透压对L-丙氨酸的影响 溶质以及乙醇是否会减少溶质；4)确定 细胞中氯离子的被动再分布是否由电压驱动 渗透诱导的细胞跨膜电位的变化，这是 构成了一种控制细胞体积的新手段。成功 该项目的完成将扩大我们对该机制的了解 肝细胞体积调节。此外，这些与健康相关的 研究将产生关于慢性和慢性疾病的新信息 乙醇的急性效应抑制了肝细胞体积调节，这种调节在 转而导致细胞肥大，肝肿大，以及 肝功能恶化。

The long-term goals of this proposal are to elucidate the failure of hepatocyte volume regulation during chronic ethanol ingestion, which results in hepatomegaly. Liver enlargement in turn leads to portal hypertension, impaired microcirculation, and anoxic degeneration of hepatic function. The immediate goal is to determine whether chronic ethanol ingestion in mice or acute administration of ethanol to hepatocytes in primary culture diminishes the capability of liver cells to regulate their volume. The project will utilize a novel, electrophysiological technique to measure change in hepatocyte water volume. The specific aims are 1) to determine the membrane water permeability coefficient for hepatocytes in primary culture and whether it is affected by ethanol; 2) to determine whether hepatocytes in primary monolayer culture regulate their volume in response to perturbations in external osmolality and whether volume regulation diminishes with chronic and acute effects of ethanol; 3) to determine whether rapid volume regulation in cultured hepatocytes facilitates secondary active transport of L-alanine by compensating for the osmolality of accumulated organic solute and whether this diminishes due to ethanol; 4) to determine whether passive, redistribution of cellular Cl- is voltage-driven by osmotically-induced changes in cell transmembrane potential, which constitutes a novel means for control of cell volume. Successful completion of this project will expand our knowledge of the mechanisms of hepatocyte volume regulation. Moreover, the health-relatedness of these studies will be the generation of new information on how chronic and acute effects of ethanol inhibit hepatocyte volume regulation, which in turn results in cell hypertrophy, hepatomegaly, and the sequelae of deteriorated hepatic function.