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.
| Arany, Szilvia; Benoit, Danielle S W; Dewhurst, Stephen et al. (2013) Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo. Mol Ther 21:1182-94 |
| Arany, Szilvia; Xu, Qingfu; Hernady, Eric et al. (2012) Pro-apoptotic gene knockdown mediated by nanocomplexed siRNA reduces radiation damage in primary salivary gland cultures. J Cell Biochem 113:1955-65 |
| Yates 3rd, John R; Park, Sung Kyu Robin; Delahunty, Claire M et al. (2012) Toward objective evaluation of proteomic algorithms. Nat Methods 9:455-6 |
| Rugel-Stahl, Anastasia; Elliott, Marilyn E; Ovitt, Catherine E (2012) Ascl3 marks adult progenitor cells of the mouse salivary gland. Stem Cell Res 8:379-87 |
| 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 |
| Arany, Szilvia; Catalan, Marcelo A; Roztocil, Elisa et al. (2011) Ascl3 knockout and cell ablation models reveal complexity of salivary gland maintenance and regeneration. Dev Biol 353:186-93 |
| 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 |
Showing the most recent 10 out of 47 publications
