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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.

酒精相关疾病和障碍（ADD）占全球健康问题的5%以上，酒精