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。

基本信息

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
项目类别：
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

项目摘要

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.

酒精相关疾病和失调 (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。有证据表明肠上皮紧密连接破坏和粘膜屏障功能障碍酒精性内毒素血症、全身性炎症和 ADD 的先决步骤是该领域的一个关键障碍。因此，目前酒精引起的紧密连接破坏的机制尚不清楚。 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 的治疗方法。 ADD 的病理生理学并通过针对肠道屏障功能障碍开发新的治疗策略。 CaV1.3和CaV1.3是肠上皮顶膜上的Ca2+渗透性离子通道。初步研究表明： 1) 钙离子从顶膜流入是酒精对肠上皮紧密连接的协同破坏和屏障功能障碍2) TRPV6 或。 CaV1.3 缺乏会减弱酒精诱导的上皮通透性 3) TRPV6 是酒精诱导的所需。细胞内钙升高，4) 酒精会引起对 SOR-C13 敏感的 Caco-2 细胞中的离子电流， TRPV6 抑制剂。5) TRPV6 或 CaV1.3 缺陷小鼠对酒精诱导的肠道通透性具有抵抗力。 C13 可以防止酒精介导的上皮通透性。这些发现构成了科学前提和依据。支持 TRPV6 和 CaV1.3 通道驱动酒精诱导的内毒素血症的中心假设我们将通过破坏肠上皮 TJ 和粘膜屏障功能来抑制全身炎症。通过确定 1) TRPV6 和 CaV1.3 通道的协调活动介导来检验该假设酒精引起的肠道细胞钙含量升高，2) TRPV6 和 CaV1.3 通道介导酒精- 肠道诱导的通透性、内毒素血症和全身炎症，3) 评估预防和 SOR-C13 和地尔硫卓（钙通道阻滞剂）在酒精引起的内毒素血症中的缓解潜力这些研究的预期结果将是对这一问题有更深入的了解。肠道在 ADD 病理生理学中的作用以及合理设计的新型治疗方法的鉴定预防和治疗 ADD 的目标。