The quality of life for millions of Americans is adversely affected by salivary gland hypofunction caused by a variety of etiologies including systemic diseases, radiation therapy, xerogenic medications, and Sj6gren's syndrome. The development of interventions to restore function for these individuals requires a thorough understanding of the molecular physiology of salivary glands. Salivary secretion involves a two-step process: acinar cells initially secrete an isotonic, plasma-like fluid;duct cells subsequently modify this primary secretion to conserve NaC1. Both the fluid secretion and NaC1 reabsorption processes are dependent upon the coordinated action of multiple Na+ transport mechanisms including Na+/H+ exchangers, Na+ channels, and Na+/K+/2C1- co-transporters. Genetically modified mice have proven to be valuable models of human salivary gland dysfunction, and are useful for confirming the molecular identities and the functional properties of important Na+ transporters. Nevertheless, significant gaps remain in our understanding of the function of the major Na+ transporting proteins. To address remaining questions, we propose a molecular and functional comparison of Na+ transporter physiology in human and mouse salivary glands. We will test the overall hypothesis that Na+ transport proteins are critical to saliva formation. Specifically:
Aim 1) will take advantage of genetically modified mice generated by targeted disruption of the Na+ channel ENaC (Scrmla) and the Na+/H+ exchanger Nhe4 [Slc9a4) genes to directly test whether these Na+ transport proteins are essential for salivary gland secretion;
Aim 2) will assess whether agonists that mobilize intracellular Ca 2+, or increase the intracellular cAMP content, acutely regulate the activity of the different Na+ transport mechanisms in human and mouse salivary cells;
and Aim 8) will determine whether gene disruption affects saliva production through systemic or gland-specific mechanisms. Ultimately, the information gained from these Aims will aid in the development of therapies to remedy various forms of salivary gland dysfunction.
| Catalán, Marcelo A; Scott-Anne, Kathleen; Klein, Marlise I et al. (2011) Elevated incidence of dental caries in a mouse model of cystic fibrosis. PLoS One 6:e16549 |
| Romanenko, Victor G; Catalán, Marcelo A; Brown, David A et al. (2010) Tmem16A encodes the Ca2+-activated Cl- channel in mouse submandibular salivary gland acinar cells. J Biol Chem 285:12990-3001 |
| Catalan, Marcelo A; Nakamoto, Tetsuji; Gonzalez-Begne, Mireya et al. (2010) Cftr and ENaC ion channels mediate NaCl absorption in the mouse submandibular gland. J Physiol 588:713-24 |
| Nakamoto, Tetsuji; Brown, David A; Catalan, Marcelo A et al. (2009) Purinergic P2X7 receptors mediate ATP-induced saliva secretion by the mouse submandibular gland. J Biol Chem 284:4815-22 |
| Romanenko, Victor G; Roser, Kurt S; Melvin, James E et al. (2009) The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels. Am J Physiol Cell Physiol 296:C878-88 |
| Srivastava, Alaka; Romanenko, Victor G; Gonzalez-Begne, Mireya et al. (2008) A variant of the Ca2+-activated Cl channel Best3 is expressed in mouse exocrine glands. J Membr Biol 222:43-54 |
| Nakamoto, Tetsuji; Romanenko, Victor G; Takahashi, Atsushi et al. (2008) Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland. Am J Physiol Cell Physiol 294:C810-9 |
| Taylor, Simon R J; Gonzalez-Begne, Mireya; Dewhurst, Stephen et al. (2008) Sequential shrinkage and swelling underlie P2X7-stimulated lymphocyte phosphatidylserine exposure and death. J Immunol 180:300-8 |
| Romanenko, Victor G; Nakamoto, Tetsuji; Catalan, Marcelo A et al. (2008) Clcn2 encodes the hyperpolarization-activated chloride channel in the ducts of mouse salivary glands. Am J Physiol Gastrointest Liver Physiol 295:G1058-67 |
| Srivastava, Alaka; Wang, Jianghua; Zhou, Hui et al. (2008) Age and gender related differences in human parotid gland gene expression. Arch Oral Biol 53:1058-70 |
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