Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage.

与酒精相关的疾病和障碍(ADD)占全球健康问题的5%以上，而酒精 滥用是200多种疾病的致病因素。内毒素血症和全身炎症很常见。 与各种ADD的发病率和死亡率相关的条件。广泛的临床和实验 有证据表明，肠上皮紧密连接的破坏和粘膜屏障功能障碍是 酒精性内毒素血症、全身炎症和ADD的先决条件步骤。该领域的一个关键障碍是 酒精诱导紧密连接破坏的机制还不是很清楚。因此，当前的 ADD的治疗仍然是经验性的(例如，皮质类固醇)。我们的长期目标是描述 ADD的病理生理学和通过靶向肠道屏障功能障碍开发新的治疗策略。TRPV6 和CaV1.3是肠上皮细胞顶膜上的钙离子通道。我们的 初步研究表明：1)根尖膜钙离子内流是牙周炎发生的必要条件 酒精协同破坏肠上皮紧密连接和屏障功能障碍。2)TRPV6或 CaV1.3缺乏可减弱酒精诱导的上皮通透性。3)酒精诱导需要TRPV6 细胞内钙升高，4)酒精引起对SOR-C13敏感的Caco-2细胞的离子电流 TRPV6抑制剂。5)TRPV6或CaV1.3基因缺陷小鼠对酒精诱导的肠通透性具有抵抗力。6)SOR- C13可阻止酒精介导的上皮通透性。这些发现构成了科学前提和 支持TRPV6和CaV1.3通道驱动酒精诱导的内毒素血症和 通过加强肠上皮TJ破坏和粘膜屏障功能障碍而引起的全身性炎症。我们会 通过确定1)TRPV6和CaV1.3通道的协调活动中介来检验这一假设 酒精诱导肠道细胞钙升高，2)TRPV6和CaV1.3通道介导酒精- 诱导的肠通透性、内毒素血症和全身性炎症，以及3)评估预防和 钙通道阻滞剂SOR-C13和地尔硫卓对酒精性内毒素血症的缓解作用 和系统性反应。这些研究的预期结果将是对 肠道在ADD病理生理机制中的作用及合理设计新疗法的确定 ADD的防治目标。

Alcohol-related diseases and disorders (ADD) account for over 5% of global health problems, and alcohol abuse is a causal factor in more than 200 diseases. Endotoxemia and systemic inflammation are common conditions associated with morbidity and mortality in various ADD. Extensive clinical and experimental evidence indicates that disruption of intestinal epithelial tight junction and mucosal barrier dysfunction are prerequisite steps in alcoholic endotoxemia, systemic inflammation, and ADD. A critical barrier in the field is that the mechanisms of alcohol-induced tight junction disruption are poorly defined. Hence, the current treatment for ADD remains empiric (e.g., corticosteroids). Our long-term goal is to describe the pathophysiology of ADD and develop novel therapeutic strategies by targeting gut barrier dysfunction. TRPV6 and CaV1.3 are Ca2+ permeable ion channels on the apical membrane of the intestinal epithelium. Our preliminary studies have identified that: 1) Calcium influx from the apical membrane is required for the synergistic disruption of intestinal epithelial tight junction and barrier dysfunction by alcohol. 2) TRPV6 or CaV1.3 deficiency attenuates alcohol-induced epithelial permeability. 3) TRPV6 is required for alcohol-induced elevation of intracellular calcium, 4) Alcohol evokes ionic currents in Caco-2 cells sensitive to SOR-C13, a TRPV6 inhibitor. 5) TRPV6 or CaV1.3 deficient mice are resistant to alcohol-induced gut permeability. 6) SOR- C13 prevents the alcohol-mediated epithelial permeability. These findings form the scientific premise and support the central hypothesis that TRPV6 and CaV1.3 channels drive alcohol-induced endotoxemia and systemic inflammation by enforcing intestinal epithelial TJ disruption and mucosal barrier dysfunction. We will test this hypothesis by determining that 1) the coordinated activities of TRPV6 and CaV1.3 channels mediate alcohol-induced rise in cellular calcium in the intestine, 2) TRPV6 and CaV1.3 channels mediate alcohol- induced gut permeability, endotoxemia, and systemic inflammation, and 3) evaluate the preventive and mitigating potential of SOR-C13 and diltiazem, the calcium channel blockers, in alcohol-induced endotoxemia and systemic response. The expected outcome of these studies will be a deeper understanding of the intestine’s role in the pathophysiology of ADD and the identification of rationally designed novel therapeutic targets for the prevention and treatment of ADD.