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Principal Investigator: RADHAKRISHNA RAO
Organization: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
Fiscal Year: 2024
Award: $495,570
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <21+ years old><Absolute ethanol><Acetaldehyde><Adrenal Cortex Hormones><Adult><Adult Human><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcoholic><Alcoholic Liver Diseases><Alcoholic liver damage><Alcohols><American><Attenuated><Binding Sites><Body Tissues><Boozer><CaCo2><CaT1 calcium channel><Caco-2 Cells><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Channel Blockers><Calcium Channel Blocking Drugs><Calcium Ion Channels><Cell Body><Cell Line><CellLine><Cells><Cellular biology><Chronic><Clinical><Combining Site><Corticoids><Corticosteroids><Degenerative Neurologic Disorders><Dependent drinker><Diltiazem><Disease><Disorder><Dysfunction><ETOH><Endotoxemia><Epithelium><EtOH abuse><EtOH drinking><EtOH use><Ethanal><Ethanol><Ethyl Alcohol><Exogenous Calcium Antagonists><Exogenous Calcium Blockaders><Exogenous Calcium Inhibitors><Feedback><Functional disorder><Glucocorticoids><Goals><Grain Alcohol><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><Hepatic Disorder><Hepatitis><Image><Injury to Liver><Intestinal><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal permeability><Intestines><Ion Channel><Ionic Channels><KO mice><Knock-out Mice><Knockout Mice><Link><Liver diseases><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Membrane Channels><Methylcarbinol><Mice><Mice Mammals><Modeling><Molecular><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Null Mouse><Occluding Junctions><Organ><Organoids><Outcome Study><Pancreatitis><Patients><Permeability><Physiopathology><Prevention><Preventive><Qualifying><Reactive Site><Resistance><Role><Strains Cell Lines><Structure><TRPV6 channel><Testing><Therapeutic><Therapeutic Agents><Tight Junctions><Tissues><Transgenic Mice><VDCC><Voltage-Dependent Calcium Channels><Zonula Occludens><adulthood><alcohol abuse therapy><alcohol abuse treatment><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol liver damage><alcohol misuse><alcohol prevention><alcohol problem><alcohol product use><alcohol related liver disease><alcohol treatment><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic damage><alcohol-induced hepatic dysfunction><alcohol-induced liver damage><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><analog><apical membrane><attenuate><attenuates><bowel><calcium antagonist><cell biology><channel blockers><chronic EtOH drinking><chronic alcohol consumption><chronic alcohol drinking><chronic alcohol ingestion><chronic alcohol use><chronic ethanol consumption><chronic ethanol drinking><chronic ethanol ingestion><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><ethanol abuse><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol misuse><ethanol product use><ethanol use><ethanol-induced hepatic damage><ethanol-induced hepatic dysfunction><ethanol-induced liver damage><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><global health><hazardous alcohol use><hepatic damage><hepatic disease><hepatic injury><hepatopathy><imaging><in vivo><inhibitor><injury to tissue><intestinal barrier><intestinal epithelium><intestinal mucosal barrier><knock-down><knockdown><liver damage><liver disorder><liver injury><mortality><mouse model><murine model><neurodegenerative illness><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><patch clamp><pathophysiology><pharmacologic><prevent><prevent alcohol><preventing><preventing alcohol><problem alcohol use><problem drinker><problem drinking><problematic alcohol consumption><problematic alcohol use><rational design><resistant><response><side effect><social role><systemic inflammation><systemic inflammatory response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tissue injury><unhealthy alcohol use><voltage>