The Secretory Mechanisms and Dysfunction Section investigates the molecular nature and function of the ion transport mechanisms involved in the fluid and electrolyte secretion process in the exocrine salivary gland. We are probing the structure-function relationships of cotransporter, exchanger and channel proteins using a combination of molecular biology, gene modification, proteomics and functional studies in mouse and human salivary glands. We are using a high-throughput approach to catalogue the human saliva proteome, to identify salivary biomarkers for human diseases, and to compile a comprehensive list of the plasma membrane proteins expressed in salivary glands. Accomplishments/conclusions: Mice lacking ClC-2 channels have a severe defect in absorptive ion transport in the distal colon. This is the first demonstration of the function of ClC-2 in NaCl absorption. We performed a quantitative salivary proteomic survey of patients with chronic Graft-versus-Host Disease (cGvHD). Clear differences were observed in the saliva of cGvHD patients with oral manifestations compared to those with no oral pathology. A quantitative proteomic analysis of parotid saliva revealed differences in expression consistent with the immunological disease status of Primary Sjgrens Syndrome patients. The TRPV4 receptor-channel was found to modulate Ca2+ influx in acinar cells and to stimulate salivation in the mouse submandibular gland. As part of a team effort, a quantitative model of electrolyte exchange was developed that can explain salivary ductal function.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$1,788,177
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
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Gao, Xin; Oei, Maria S; Ovitt, Catherine E et al. (2018) Transcriptional profiling reveals gland-specific differential expression in the three major salivary glands of the adult mouse. Physiol Genomics 50:263-271
Mukaibo, Taro; Munemasa, Takashi; George, Alvin T et al. (2018) The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells. J Biol Chem 293:6259-6268
Vera-Sigüenza, Elías; Catalán, Marcelo A; Peña-Münzenmayer, Gaspar et al. (2018) A Mathematical Model Supports a Key Role for Ae4 (Slc4a9) in Salivary Gland Secretion. Bull Math Biol 80:255-282
Mukaibo, T; Munemasa, T; Masaki, C et al. (2018) Defective NaCl Reabsorption in Salivary Glands of Eda-Null X-LHED Mice. J Dent Res 97:1244-1251
Alevizos, I; Zheng, C; Cotrim, A P et al. (2017) Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther 24:176-186
Yang, Chengtao; Gonzalez-Perez, Vivian; Mukaibo, Taro et al. (2017) Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells. Proc Natl Acad Sci U S A 114:E3739-E3747
Jalali, Rozita; Lodder, Johannes C; Zandieh-Doulabi, Behrouz et al. (2017) The Role of Na:K:2Cl Cotransporter 1 (NKCC1/SLC12A2) in Dental Epithelium during Enamel Formation in Mice. Front Physiol 8:924
Peña-Münzenmayer, Gaspar; George, Alvin T; Shull, Gary E et al. (2016) Ae4 (Slc4a9) is an electroneutral monovalent cation-dependent Cl-/HCO3- exchanger. J Gen Physiol 147:423-36
Henríquez, C; Riquelme, T T; Vera, D et al. (2016) The calcium-activated potassium channel KCa3.1 plays a central role in the chemotactic response of mammalian neutrophils. Acta Physiol (Oxf) 216:132-45
Wang, Ching-Shuen; Wee, Yinshen; Yang, Chieh-Hsiang et al. (2016) ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland. Sci Rep 6:24244

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