Calcium is a key regulator of a broad range of biological functions and is also a key element in the composition of dental enamel. During the maturation stage of amelogenesis, Ca2+ requirements increase as enamel crystals expand in width and thickness. Calcium must reach the forming enamel layer but how this process is regulated in ameloblasts is poorly understood. The current model for Ca2+ transport in enamel focuses on the transcellular passage of Ca2+ via the entry, transit and extrusion steps. Whereas several works have reported on the transit and extrusion steps, only limited information is available for Ca2+ entry mechanisms into ameloblasts. In this grant proposal, I focus on the entry step by examining the role of the store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels comprise important Ca2+ influx mechanism in epithelial cells. Patients with mutations to CRAC channels (STIM1, ORAI1) present, in addition to immune system deficiencies, with hypocalcified amelogenesis imperfecta. My goal is to identify how Stim1 and Orai1 are involved in Ca2+ entry and how this process is regulated. Recent work by the PI indicates that Stim1, Orai1 as well as well as the Ca2+ signaling cholecystokinin (Cck) and the Cck inhibitor Rcan1 were identified as being significantly up-regulated in maturation. I have confirmed these results by qPCR, Western blot and IHC. Thus Ca2+ influx into ameloblasts via CRAC channels and how this process is regulated is important for the development of healthy enamel. Evidence contributed by the proposed grant application will help to better understand the systemic effects of CRAC function abrogation. This will also help medical practitioners in making decisions concerning dentist visits to patients with mutations to CRAC channels in order to prevent dental problems

Public Health Relevance

/Relevance to Public Health Calcium is critical for the normal biomineralization of enamel. Disruptions to calcium uptake by ameloblasts results in amelogenesis imperfecta. My goal is to analyze the function of calcium-store operated channels in enamel development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Transition Award (R00)
Project #
4R00DE022799-03
Application #
8733843
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wan, Jason
Project Start
2014-02-24
Project End
2017-01-31
Budget Start
2014-02-24
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$473,101
Indirect Cost
$173,512
Name
New York University
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Wen, Xin; Lacruz, Rodrigo S; Smith, Charles E et al. (2014) Gene-expression profile and localization of Na+/K(+)-ATPase in rat enamel organ cells. Eur J Oral Sci 122:21-6