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：
10390126
负责人：
RADHAKRISHNA RAO
金额：
$ 50.49万
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/10390126
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 Epithelial Ethanol Feedback Functional disorder Glucocorticoids Goals Hepatitis Intestinal permeability Intestines Ion Channel Knockout Mice Link Liver diseases Mediating Modeling Molecular Morbidity - disease rate Mucous Membrane Mus Neurodegenerative Disorders Organ Organoids Outcome Study Pancreatitis Patients Permeability Pharmacology Prevention Preventive 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 mass spectrometric imaging mortality mouse model new therapeutic target novel novel therapeutic intervention patch clamp 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.

与酒精有关的疾病和疾病（ADD）占全球健康问题的5％以上虐待是200多种疾病的因果因素。内毒素血症和全身性炎症很常见各种添加的发病率和死亡率相关的条件。广泛的临床和实验证据表明肠上皮紧密连接和粘膜障碍功能障碍的破坏是酒精性内毒素，全身感染和添加的先决条件。该领域的关键障碍是酒精引起的紧密连接破坏的机制的定义很差。因此，电流添加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通过靶向肠道屏障功能障碍来添加和发展新型治疗策略的病理生理学。 TRPV6 Cav1.3是肠上皮顶膜上的Ca2+渗透离子通道。我们的初步研究已经确定：1）钙来自顶膜的钙影响是需要的酒精对肠上皮紧密连接和屏障功能障碍的协同破坏。 2）TRPV6或 CAV1.3缺乏减弱了酒精引起的上皮渗透性。 3）酒精引起的TRPV6是必需的细胞内钙的升高，4）酒精唤起对CACO-2细胞对SOR-C13敏感的离子电流，A TRPv6抑制剂。 5）TRPV6或CAV1.3缺乏的小鼠对酒精诱导的肠道渗透性有抵抗力。 6）sor- C13防止酒精介导的上皮渗透性。这些发现构成了科学前提，支持TRPV6和CAV1.3通道驱动酒精引起的内毒素血症和通过执行肠上皮TJ破坏和粘膜屏障功能障碍来进行全身炎症。我们将通过确定1）TRPV6和CAV1.3通道的协调活动来检验该假设酒精诱导的肠中细胞钙升高，2）TRPV6和CAV1.3通道介导酒精 - 诱导肠道通透性，内毒素血症和全身性炎症，3）评估预防性和在酒精引起的内毒素血症中，钙通道阻滞剂的SOR-C13和Diltiazem的潜力减弱和系统性响应。这些研究的预期结果将是对肠在ADD的病理生理学和合理设计的新型疗法中的作用预防和治疗的目标。