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FUNCTION OF TRPC3 IN SALIVARY GLAND

Award Number: R03DE019524
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2010
PERIOD OF PERFORMANCE END DATE: 04/30/2012

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FUNCTION OF TRPC3 IN SALIVARY GLAND - DESCRIPTION (provided by applicant): Salivary gland acinar cells secrete high levels of calcium together with salivary proteins and fluids. This saliva then travels down the ductal system till it reaches the oral cavity. Salivary ducts have minimal secretory function and are proposed to be involved in reabsorption of ions such as Na+. It is presently unclear whether salivary gland ducts, like exocrine pancreatic ducts; reabsorb calcium since [Ca2+] in saliva is high. Some earlier reports show that there is a gradient in decrease in [Ca2+] in the saliva while flowing though the ductal lumen. Therefore we propose that salivary ductal cells might reabsorb Ca2+ since maintaining the calcium levels is essential for the maintenance of salivary flow through the ductal lumen. Furthermore, high saliva calcium has been suggested to be a contributing factor to the salivary gland stone formation or sialoliths. Stone formation in salivary duct is the most common disease of salivary glands that is caused by the formation of salivary calculi consisting of mainly calcium phosphate due to the presence of higher concentration of calcium. It is important to note that in tissues such as kidney, stone formation is associated with changes in calcium reabsorption. Whether calcium reabsorption via salivary gland ducts is involved in modulating calcium levels in saliva is not yet known. TRPC3, a Ca2+ entry channel is predominantly localized in apical membrane in the ducts of the SMG. CSR, a G-protein coupled receptor is also present in the same region of salivary gland ducts where it appears to associate with TRPC3. Our central hypothesis is that calcium in saliva secreted from acinar cells activates the CSR while flowing through the ductal system that potentially modulate the Ca2+ influx via TRPC3 channel. This would result in transepithelial calcium flux across the salivary ductal cell. We suggest that such regulation of saliva calcium concentration serve to protect salivary duct from calcium stone formation. This research addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Furthermore, data obtained from the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva. Finally, the findings will also reveal whether salivary glands have inherent autoregulatory mechanisms, which prevent salivary gland dysfunction due to ductal obstructions. Thus we believe our concept is innovative and the proposed research is novel. Information gained from this study will not only help understanding basic aspects of ductal cell function but will also reveal mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. Future direction: Present study will help to understand the role of TRPC3 in Ca2+ entry into the salivary ductal cells. This Ca2+ influx could be a mechanism of Ca2+ reabsorption in salivary ductal cells. Based on the results obtained from this study, we will build up a bigger project to understand the cellular and molecular basis of the development of calcium stone formation and this will be extremely helpful to prevent sialolithiasis. Furthermore, this study and the future project will also help to identify the potential candidates to develop new drugs for the above clinical condition. Public Health Relevance: Sialolithiasis, stone formation in salivary duct due to blockage of salivary duct is the most common disease of salivary glands. It is estimated to affect 12 in 1000 of the adult population and accounts for more than 50% of diseases of the large salivary glands. Present study will help to understand the mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. This research is very important since high saliva calcium has been suggested to be a contributing factor to the formation of sialoliths. This research also addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Additionally, the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $83,589 )
2011	2011	INSTITUTE FOR CLINICAL RESEARCH, INC	POST OFFICE BOX 29545	WASHINGTON	DC	20017	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	003	3	5/26/2011	NON-COMPETING CONTINUATION	$938
2011	2011	INSTITUTE FOR CLINICAL RESEARCH, INC	POST OFFICE BOX 29545	WASHINGTON	DC	20017	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	002	3	5/20/2011	NON-COMPETING CONTINUATION	$92,887
2011	2010	INSTITUTE FOR CLINICAL RESEARCH, INC	POST OFFICE BOX 29545	WASHINGTON	DC	20017	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	001	2	4/29/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,696
2011	2010	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	1	4/15/2011	NEW	-$51,932
														Subtotal = $83,589

Issue Date FY: 2010 ( Subtotal = $115,125 )
2010	2010	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	1	4/21/2010	NEW	$115,125
														Subtotal = $115,125

Grand Total All Awards = $198,714

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FUNCTION OF TRPC3 IN SALIVARY GLAND

Award Number: R03DE019524

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2010

PERIOD OF PERFORMANCE END DATE: 04/30/2012

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