Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 2 million people in the U.S. is compromised by from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is well established that calcium is the primary intracellular factor which regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the absence of information regarding the calcium channels present in salivary glands. Moreover, in Sjogren's syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Members of the Transient Receptor Potential (TRP) superfamily have been identified as calcium channels, which could be important in agonist-stimulated fluid secretion. Therefore, this study is designed to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential (TRPC1) protein-1 and saliva secretion. Our preliminary data indicates that TRP proteins are expressed in salivary glands and are involved in salivary secretion. The hypothesis of this study is that since calcium plays a pivotal role in the physiological function of salivary glands, characterization of calcium channels in salivary glands will be important to understand the mechanism of saliva secretion, which could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of TRPC1 channel protein by examining its effect by gene disruption using TRPC1 knockout mice.
In Aim 2, we will investigate the localization and biochemical characterization of TRPC1 protein in mouse submandibular gland cells.
Aim 3 will identify the mechanism involved in the regulation of TRPC1 protein. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in saliva secretion. Greater understanding of these events responsible for saliva secretion will be important in elucidating new therapy for salivary gland dysfunction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE017102-01A1
Application #
7139887
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Shum, Lillian
Project Start
2006-07-01
Project End
2011-04-30
Budget Start
2006-07-01
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$244,300
Indirect Cost
Name
University of North Dakota
Department
Biochemistry
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Krout, Danielle; Schaar, Anne; Sun, Yuyang et al. (2017) The TRPC1 Ca2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes. J Biol Chem 292:20799-20807
Sun, Yuyang; Zhang, Haopeng; Selvaraj, Senthil et al. (2017) Inhibition of L-Type Ca2+ Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons. J Neurosci 37:3364-3377
Sukumaran, Pramod; Schaar, Anne; Sun, Yuyang et al. (2016) Functional role of TRP channels in modulating ER stress and Autophagy. Cell Calcium 60:123-32
Selvaraj, Senthil; Sun, Yuyang; Sukumaran, Pramod et al. (2016) Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol Carcinog 55:818-31
Madeo, Marianna; Stewart, Michelle; Sun, Yuyang et al. (2016) Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy. Am J Hum Genet 98:1249-1255
Schaar, Anne; Sukumaran, Pramod; Sun, Yuyang et al. (2016) TRPC1-STIM1 activation modulates transforming growth factor ?-induced epithelial-to-mesenchymal transition. Oncotarget 7:80554-80567
Sun, Yuyang; Birnbaumer, Lutz; Singh, Brij B (2015) TRPC1 regulates calcium-activated chloride channels in salivary gland cells. J Cell Physiol 230:2848-56
Sukumaran, P; Sun, Y; Vyas, M et al. (2015) TRPC1-mediated Ca²? entry is essential for the regulation of hypoxia and nutrient depletion-dependent autophagy. Cell Death Dis 6:e1674
Zhou, Xikun; Ye, Yan; Sun, Yuyang et al. (2015) Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase C? Signaling. Mol Cell Biol 35:2729-39
Chauhan, Arun; Quenum, Fredice Z; Abbas, Ata et al. (2015) Epigenetic Modulation of Microglial Inflammatory Gene Loci in Helminth-Induced Immune Suppression: Implications for Immune Regulation in Neurocysticercosis. ASN Neuro 7:

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