Salivary gland function is essential for oral and general health, and oral diseases that diminish saliva production significantly impact one's quality of life. Sympathetic and parasympathetic input to salivary glands rapidly and dynamically control the rate of salivary flow by the coordinated activities of ion channels and transporters that induce water movement and promote the exocytotic secretion of digestive enzyme and other proteins. This control is achieved by mechanisms that generate complex patterns of cytosolic Ca2+ observed in acinar cells. Whereas the consequences of these signals for fluid and protein secretion are subjects of on- going investigations, the potential role that acidic vacuolar Ca2+ stores play in the triggering or globalization of receptor mediated Ca2+ signals has not yet been appreciated. The identification of acidic, vacuolar organelles as a releasable Ca2+ store in some cells was revealed by the discovery that nicotinic acid adenine dinucleotide phosphate (NAADP) functions as a newly recognized highly potent Ca2+ mobilizing messenger that initiates or sensitizes agonist-stimulated Ca2+ signals in a variety of mammalian cells. However, it is surprising that our knowledge of this newly elaborated fundamental Ca2+ signaling pathway lags when compared to some other exocrine organs. The central hypothesis is that NAADP-evoked Ca2+ release from acidic compartments exerts critical regulatory control over salt and protein secretion in parotid acinar cells. The goal of the proposal is to elucidate the role of this novel pathway in salivation by directly measuring saliva flow in normal (background strain) and mouse models of Sjgren's syndrome (SS). This will be achieved in combination with pharmacological interventions or by measuring Ca2+ and secretory dynamics in parotid and submandibular acinar cell clusters, organ slices or live animals. In addition, the role of NAADP in Ca2+ and secretory dynamics will also be assessed in parotid and submandibular tissues obtained following surgery from healthy or SS patients. The working hypothesis is that diminished NAADP signaling plays an important role in SS. We will i) demonstrate agonist-induced formation of NAADP, ii) identify the relevant molecular machinery for NAADP-mediated signaling and iii) elucidate the functional consequences of NAADP to Ca2+ signals in parotid acini. Importantly, this work will advance our understanding of fundamental signaling pathways relevant for salivary gland function and identify potential targets for augmenting or restoring function for patients suffering reduced saliva formation.
Diminished saliva production and dry mouth sensation have a profound impact on oral health and quality of life. Although patients can benefit from treatments that stimulate residual secretory capacity, current treatments generally provide only temporary relief. Using a variety of biochemical, optical and electrophysiological approaches to investigate a newly appreciated, novel cell signal for stimulating saliva-producing cells we will identify new potential targets for augmenting or restoring function for patients suffering reduced saliva formation.
|Marvin, Rachel K; Saepoo, Muncharie B; Ye, Simiao et al. (2017) Salivary protein changes in response to acute stress in medical residents performing advanced clinical simulations: a pilot proteomics study. Biomarkers 22:372-382|
|Imbery, John F; Bhattacharya, Sumit; Khuder, Sura et al. (2016) cAMP-dependent recruitment of acidic organelles for Ca2+ signaling in the salivary gland. Am J Physiol Cell Physiol 311:C697-C709|
|Ghanem, Simona S; Heinrich, Garrett; Lester, Sumona G et al. (2016) Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem 291:980-8|
|Ali, Ramadan A; Camick, Christina; Wiles, Katherine et al. (2016) Nicotinic Acid Adenine Dinucleotide Phosphate Plays a Critical Role in Naive and Effector Murine T Cells but Not Natural Regulatory T Cells. J Biol Chem 291:4503-22|
|Bhattacharya, Sumit; Imbery, John F; Ampem, Prince Tuffour et al. (2015) Crosstalk between purinergic receptors and canonical signaling pathways in the mouse salivary gland. Cell Calcium 58:589-97|