Pathophysiology of Sodium/Bicarbonate Transporters

We study physiology and pathophysiology of the sodium/bicarbonate transporters which move bicarbonate into cells and regulate intracellular pH, as well as transepithelial movement of HCO3. These proteins are members of SLC4A family proteins and play essential roles in acid-base regulation of epithelial and nonepithelial cells in a variety of organs.  Two main projects are currently ongoing.

Project 1: Examine the role of brain pH in alcohol consumption

Excessive alcohol drinking can harm our health. A recent study shows that during 2011-2015 excessive drinking was responsible for >95,000 deaths, and excessive drinking led to 1 in 10 deaths among adults aged 20–64 years. Limiting the frequency and amount of alcohol consumption is recommended to minimize the risk of developing the alcohol use disorder. The current medical treatments approved by the FDA are prescribed only to people who have already stopped drinking and are trying to maintain abstinence. For ordinary drinkers, it is best simply to cut back drinking. Many people benefit simply by controlling their drinking habits, such as drinking slowly, choosing alcohol-free days, or setting a limit on how much you will drink, as recommended by the NIH. Nonetheless, maintaining new drinking habits is not an easy task and some people attain their goal only to find that old habits appear again later. Thus, a non-medication strategy to reduce alcohol consumption is demanded to people who want to drink moderately.

We recently reported that pH can affect alcohol reward value or alcohol modulatory properties, thus changing alcohol consumption. Knockout mice lacking the sodium bicarbonate transporter NBCn1 have a lower pH in plasma and cerebrospinal fluid and, more importantly, drink more alcohol than control mice. They drink more alcohol as their motivation to drink is enhanced. Furthermore, restoring normal blood pH by bicarbonate ingestion suppresses increased alcohol consumption. This observation is interesting because by adjusting body pH we can control the amount of alcohol consumed. We are currently developing a research platform that will ultimately move toward commercializing a non-prescription food supplement for managing alcohol consumption. The project recognizes systemic pH as a physiological factor that can change alcohol consumption. We anticipate that the project will provide unprecedented information on the decreasing effect of bicarbonate on alcohol consumption and lead to a non-medication strategy for drinkers to control their drinking. Food products have a lower risk of adverse effects compared to medical preparations. This project is a new approach to reducing alcohol consumption and is not currently being tested by other investigators or industries.

NBCn1 knockout increases alcohol consumption in mice. A) Alcohol consumption. B) alcohol preference. C) Schematic timeline for repeated alcohol withdrawal. D) Alcohol consumption after repeated withdrawal.

Project 2: Examine the pathophysiology of sodium bicarbonate transporters in human prostate cancer

Cancer is developed from genetic and epigenetic changes in normal cells, and environmental and systemic stresses assist tumor initiation or aggravation. The microenvironment surrounding tumors is acidic due to increased metabolic activity, excessive CO2 production, and poor oxygenation. Under such acidic conditions, tumor cells undergo adaptations and this adaptation promotes survival, proliferation, expansion, and metastasis. Because acidic pH is favorable for tumor cells, disrupting such acidic microenvironments is expected to reduce or delay cancer cell growth.

This project focuses on the role of the sodium bicarbonate transporters in cancer growth. The sodium bicarbonate transporters move HCO3 into cells and regulate cellular pH. In normal cells, this bicarbonate influx has negligible effect on extracellular pH as a large reservoir of bicarbonate in blood is available. In tumors, however, a blood supply is limited and the amount of bicarbonate surrounding cancer cells is low as bicarbonate moves to cancer cells. Thus, inhibiting these transporters pharmacologically or by knockdown reduces cancer cell progression. The second project in our lab aims at understanding the effects of this inhibition on prostate cancer growth and developing the transporter proteins as targets that retard prostate cancer progression. By inhibiting HCO3 movement via transporters,

Immunohistochemical analysis of NBCe1 in human prostate tissue and prostatic adenocarcinoma. A) NBCe1 staining in prostatic glandular epithelia. B & C) NBCe1 staining in acinar adenocarcinoma D-F) NBCe1 staining in duct adenocarcinoma.

The project is related to an age-related health issue. Progressively worsening acidosis with age has deleterious effects over time and contributes to the pathogenesis of many age-related disturbances or disease progression. The risk of prostate cancer increases with age as metabolic acidosis is getting worse. Thus, this project may provide a pathological connection of the two age-related health issues.