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

定义肠道钙通道在酒精性肝损伤中的作用。

• 批准号: 10590757
• 负责人: RADHAKRISHNA RAO
• 金额: $ 50.35万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590757
• 关键词: Acetaldehyde; Adrenal Cortex Hormones; Adult; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; American; Attenuated; Binding Sites; CaT1 calcium channel; Caco-2 Cells; Calcium; Calcium Channel; Calcium Channel Blockers; Cell Line; Cells; Cellular biology; Chronic; Clinical; Diltiazem; Disease; Endotoxemia; Epithelium; Ethanol; Feedback; Functional disorder; Glucocorticoids; Goals; Hepatitis; Image; Intestinal permeability; Intestines; Ion Channel; Knockout Mice; Link; Liver diseases; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Neurodegenerative Disorders; Organ; Organoids; Outcome Study; Pancreatitis; Patients; Permeability; Prevention; Preventive; Qualifying; Resistance; Role; Structure; Testing; Therapeutic; Therapeutic Agents; Tight Junctions; Tissues; Transgenic Mice; alcohol abuse therapy; alcohol misuse; alcohol prevention; analog; apical membrane; channel blockers; chronic alcohol ingestion; global health; in vivo; inhibitor; intestinal barrier; intestinal epithelium; knock-down; liver injury; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; patch clamp; pharmacologic; prevent; problem drinker; rational design; response; side effect; systemic inflammatory response; targeted treatment; therapeutic target; tissue injury; voltage

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.

酒精相关疾病和障碍（ADD）占全球健康问题的5%以上， 虐待是200多种疾病的致病因素。内毒素血症和全身炎症是常见的 与各种ADD的发病率和死亡率相关的条件。 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、全身性炎症和ADD的先决条件。该领域的一个关键障碍是 酒精诱导的紧密连接破坏的机制尚不清楚。所以现在的 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 研究ADD的病理生理学，并通过靶向肠道屏障功能障碍开发新的治疗策略。TRPV6 CaV1.3是肠上皮细胞顶膜上的Ca ~（2+）可透过的离子通道。我们 初步研究已经确定：1）来自顶膜的钙内流是需要的， 酒精协同破坏肠上皮紧密连接和屏障功能障碍。2)TRPV 6或 CaV1.3缺乏减弱酒精诱导的上皮通透性。3)TRPV 6是酒精诱导的 升高细胞内钙，4）酒精在对SOR-C13敏感的Caco-2细胞中引起离子电流，a TRPV 6抑制剂。5)TRPV 6或CaV1.3缺陷型小鼠对酒精诱导的肠道通透性具有抗性。6)SOR- C13阻止酒精介导的上皮通透性。这些发现构成了科学前提， 支持TRPV 6和CaV1.3通道驱动酒精诱导的内毒素血症的中心假设， 通过加强肠上皮TJ破坏和粘膜屏障功能障碍引起全身性炎症。我们将 通过确定1）TRPV 6和CaV 1.3通道介导的协调活性来检验这一假设， 酒精诱导的肠细胞钙升高，2）TRPV 6和CaV1.3通道介导酒精- 诱导的肠道通透性、内毒素血症和全身性炎症，以及3）评价预防性和 钙通道阻滞剂SOR-C13和地尔硫卓对酒精诱导的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更深入地了解 肠道在ADD病理生理学中的作用以及合理设计的新型治疗药物的鉴定 注意缺陷障碍的防治目标。