Amelogenesis imperfecta (AI) is a group of diverse inherited disorders most often considered as a single trait and not often associated with syndromes or metabolic disorders. However, there have been documented case reports in which AI has been identified in patients with inherited proximal renal tubular acidosis. These reports identify enamel anomalies directly related to this condition of pH control affecting kidney function. We have initiated studies to better understand what role transcellular bicarbonate (HCO3-) transport plays in acid/base transport and pH control during enamel formation. We have found that two proteins involved in acid/base transport are expressed in polarized ameloblasts during amelogenesis. These two proteins are the anion exchanger (AE2) and the electrogenic sodium bicarbonate cotransporter (NBCe1). Our preliminary data shows that NBCe1 is expressed at the basolateral membrane of secretory ameloblasts, whereas AE2 is expressed at the apical (secretory) membrane. These data are the first evidence that AE2 and NBCe1 are expressed in ameloblasts, in vivo, in a polarized fashion, thereby providing a mechanism for ameloblast transcellular bicarbonate secretion in the process of enamel formation and maturation. The hypothesis of this proposal is that """"""""the spatiotemporal expression profiles of AE2 and NBCe1 in ameloblast cells are highly regulated and are responsive to changing extracellular pH conditions, and any failure in proper AE2 and NBCe1 activity will result in disruptions to the enamel prismatic structure"""""""".
Five specific aims are proposed to investigate this hypothesis. These are: 1) will define the expression profiles for AE2 and NBCe1 by in situ hybridization;2) will establish the spatial location of this AE2 and an associated chloride channel (CFTR) within the secretory face of ameloblasts using immunogold labeling and high resolution TEM;3) will develop transgenic animal lines in which AE2 and NBCe1 silencing is achieved following the animals exposure to doxycyclin;4) will be a radiographic and microscopic documentation of enamel defects in animals with mutations in the AE2 and NBCe1 gene loci;and 5) will identify pH-responsive elements in the promoter regions of AE2 and NBCe1 using an appropriate reporter assay. At the conclusion of this study there will be a greater understanding of dental disease that results from disruptions to HCO3- and acid/base transport. A raised awareness of dental disease in patients with kidney disease should result greater interactions between physicians and dentists, and result in more appropriate and comprehensive treatment plans that are initiated immediately after diagnosis, and carried out in a more cost-effective manner.
Patients with hereditary kidney and eye disease, where the cause is directly related to mutations in either the AE2 or NBCe1 proteins, frequently have dental anomalies including poorly mineralized enamel. These dental defects result in a higher incidence of dental decay starting at a very early age, and because of this these patients require significantly greater dental care that a normal population. AE2 and NBCe1 are both bicarbonate transporters involved in maintaining intracellular and extracellular pH. Once complete, this proposal will better define the molecular mechanism available to dental cells to maintain correct pH balance during the stages of tooth formation.
| Yin, Kaifeng; Lin, Wenting; Guo, Jing et al. (2017) MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways-Novel Insight into the Origins of Enamel Pathologies. Sci Rep 7:44118 |
| Yin, Kaifeng; Paine, Michael L (2017) Bicarbonate Transport During Enamel Maturation. Calcif Tissue Int 101:457-464 |
| 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 |
| Sarkar, Juni; Wen, Xin; Simanian, Emil J et al. (2016) V-type ATPase proton pump expression during enamel formation. Matrix Biol 52-54:234-245 |
| Yin, Kaifeng; Lei, Yuejuan; Wen, Xin et al. (2015) SLC26A Gene Family Participate in pH Regulation during Enamel Maturation. PLoS One 10:e0144703 |
| Nurbaeva, Meerim K; Eckstein, Miriam; Concepcion, Axel R et al. (2015) Dental enamel cells express functional SOCE channels. Sci Rep 5:15803 |
| Guo, J; Lyaruu, D M; Takano, Y et al. (2015) Amelogenins as potential buffers during secretory-stage amelogenesis. J Dent Res 94:412-20 |
| Wen, Xin; Lacruz, Rodrigo S; Paine, Michael L (2015) Dental and Cranial Pathologies in Mice Lacking the Cl(-) /H(+) -Exchanger ClC-7. Anat Rec (Hoboken) 298:1502-8 |
| Yin, Kaifeng; Hacia, Joseph G; Zhong, Zhe et al. (2014) Genome-wide analysis of miRNA and mRNA transcriptomes during amelogenesis. BMC Genomics 15:998 |
| 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 |
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