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Research at Mass General
Our laboratory examines the regulation of transepithelial transport, focusing on the biology and (patho) physiology of the vacuolar proton-pumping ATPase (V-ATPase) in the kidney and other epithelia. By acidifying the extracellular environment, the V-ATPase plays a crucial role in maintaining healthy organ function and is perturbed in numerous pathological conditions. The V-ATPase is a key player in physiological processes such as acid-base homeostasis, male fertility, bone remodeling, and hearing.
The V-ATPase 56-kDa B subunit occurs in mammalian tissues as two homologous isoforms, Atp6v1b1, or "B1" (highly expressed in a restricted number of epithelia specialized for regulated H+ transport), and the ubiquitous Atp6v1b2 (“B2”) isoform. In renal collecting duct A-type intercalated cells (ICs), the B1 isoform localizes to the apical membrane and subapical domain, whereas B2 localization is less polarized. This is consistent with B1-containing V-ATPases being involved in regulated transmembrane H+ transport and B2-containing enzymes being responsible mostly for the acidification of intracellular organelles. Under certain conditions, B2-containing V-ATPase holoenzymes can be detected on the cell membrane and can mediate H+ secretion, such as in mice deficient in the B1 isoform. Understanding the mechanisms and stimuli leading to B1 and/or B2 assembly into the V-ATPase complex, and their role in V-ATPase trafficking and regulation, could offer treatment strategies for pathologies that result from loss or disruption of B1 subunit function. In general, understanding how epithelial cells respond to various stimuli by modulating the trafficking of transport proteins to and from the plama membrane is essential in approaching all diseases underlined by trafficking defects, including nephrogenic diabetes insipidus, polycystic kidney disease, cystic fibrosis, and many others.
We found that the V-ATPase is also highly expressed in the olfactory epithelium (OE). The B1 subunit isoform localizes to the apical microvilli of sustentacular cells and to the lateral membrane domain in microvillar cells. As a mediator of H+ secretion in the OE, the V-ATPase may be important for the pH homeostasis of the neuroepithelial mucous layer and/or for signal transduction in the sense of olfaction. Functional data from innate avoidance and appetitive behavior tests confirm the relevance of this enzyme in olfaction. We are now pursuing translational and clinical applications of these basic science findings, by investigating olfactory defects in kidney patients. Our goal is to develop strategies to improve these patients’ olfactory function and nutritional status.
Teodor Paunescu, PhD
Assistant Professor of Medicine
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