Calcium (Ca2+) is a key regulator of a broad range of biological functions and is also a key element in the composition of dental enamel. Ca2+ must reach the forming enamel layer but how this process is regulated in ameloblasts is poorly understood. Our goal is to identify key pathways used by ameloblasts to regulate Ca2+ dynamics, in particular the required mechanisms for Ca2+ entry and pathways activated upon increases in cytosolic Ca2+ concentration. Deficiencies in the normal functioning of these pathways result in abnormal enamel that is prone to dental disease which can act as a host environment for oral bacteria. The focus of this proposal is to identify the functions of the store operated Ca2+ release-activated Ca2+ (CRAC) channels in enamel development. CRAC channels comprise important Ca2+ influx mechanisms activated following Ca2+ release from the endoplasmic reticulum (ER). The importance of Ca2+ influx via CRAC channels pathway in ameloblasts is understood by clinical reports describing hypo-calcified amelogenesis imperfecta in patients with mutations to STIM1 and ORAI1. However our understanding of CRAC channels function in enamel is limited as Stim1-/- and Orai1-/- animals die around birth. To address this problem, we developed several conditional knockout mice that specifically analyze the function of CRAC channels with particular reference to dental enamel formation. The ensuing Ca2+ entry via CRAC activates the calcineurin-NFAT pathway, which up-regulates the regulator of calcineurin (RCAN1). Although we find that NFAT and RCAN1 are expressed in enamel cells, and that this pathway is active during enamel development, the functions of these genes in enamel development are unknown. We are particularly interested in RCAN1 as Down syndrome patients present with a host of enamel deficiencies including abnormal mineralization and thinner enamel. Down syndrome is one of the most common human genetic disorders (frequency is 1 in ~700 births) characterized by elevated levels of RCAN1 in several tissues. The cause of growth alterations in the enamel of Down syndrome patients remains unknown. Our proposed studies will increase our understanding of enamel development. Such knowledge will impact caries prevention and has broader implications in bone homeostasis/development and in the development of ectodermal organs as some of these pathways are shared. The proposed work will also lead to a better understanding of systemic effects of CRAC channel function.

Public Health Relevance

Our goal is to identify how enamel forming cells (ameloblasts) regulate Ca2+ influx and the associated pathways activated upon increases in cytosolic Ca2+. Deficiencies in the normal functioning of these mechanisms result in abnormal enamel that is prone to dental disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE025639-04
Application #
9712901
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
2016-06-07
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Other Basic Sciences
Type
Schools of Dentistry/Oral Hygn
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Fanok, Melania H; Sun, Amy; Fogli, Laura K et al. (2018) Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma. J Invest Dermatol 138:1116-1125
Lacruz, Rodrigo S (2017) Enamel: Molecular identity of its transepithelial ion transport system. Cell Calcium 65:1-7
Eckstein, Miriam; Vaeth, Martin; Fornai, Cinzia et al. (2017) Store-operated Ca2+entry controls ameloblast cell function and enamel development. JCI Insight 2:e91166
Nurbaeva, Meerim K; Eckstein, Miriam; Feske, Stefan et al. (2017) Ca2+ transport and signalling in enamel cells. J Physiol 595:3015-3039
Lacruz, Rodrigo S; Habelitz, Stefan; Wright, J Timothy et al. (2017) DENTAL ENAMEL FORMATION AND IMPLICATIONS FOR ORAL HEALTH AND DISEASE. Physiol Rev 97:939-993