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INVESTIGATING THE ROLE OF ER STRESS SENSOR IRE1α IN POSTNATAL TOOTH DEVELOPMENT

ZHOU, YUQIAO (2018) INVESTIGATING THE ROLE OF ER STRESS SENSOR IRE1α IN POSTNATAL TOOTH DEVELOPMENT. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The IRE1α/XBP1 pathway is an endoplasmic reticulum (ER) stress branch required for the development of multiple secretory cells. Whether IRE1α/XBP1 pathway regulates postnatal tooth development is unknown. Thus, my central hypothesis is that the IRE1α/XBP1 signaling pathway is an essential physiological regulator for postnatal tooth development. I used two approaches to investigate this hypothesis: (1) characterization of a mouse model and in vitro experimental follow-up, and (2) observational genetics studies in human. Firstly, I participated in generating and charactering a novel genetic mouse model carrying an Ern1 (encoding Ire1α) deletion in the odontoblastic and osteoblastic lineage cells. It was observed that the deletion of IRE1α in odontoblast lineage cells led totwo co-existing changes including (1) loss of XBP1 signaling, and (2) heightened ER stress. At the tissue level, odontoblast deficiency of IRE1α leads to compromised dentinogenesis, and at the cellular level, IRE1α-deficiency resulted in decreased odontoblast differentiation and proliferation. In addition, I found that Ire1a deficient mice displayed delayed tooth eruption of incisors and molars.
Having observed that the IRE1α /Xbp1 signaling axis is important for mineralized tissues in the mouse model, I then investigated whether human genetic variants in ERN1 and XBP1 influence dental and bone phenotypes. I employed an in silico candidate gene approach testing the genetic association of variants in ERN1 and XBP1, with tooth eruption, dental caries and bone mass phenotypes. Three different categories of genetic variants were investigated, common coding variants, common possible cis-acting regulatory variants, and low-frequency coding variants. I found a missense SNP in the ERN1 gene was significantly (p<0.05) associated with dental caries in the primary dentition. I also observed locus-wide significant associations between common possible cis-acting regulatory variants near ERN1 and XBP1 for tooth eruption, caries, and bone phenotypes (p<0.00022). The associated SNPs are in known promoter and enhancer regions in relevant cells, e.g. osteoblasts. In addition, I observed low-frequency coding variants in XBP1 were significantly associated with dental caries in the primary dentition (p<0.05). These findings provided both genetic and in vivo mouse functional evidence for the role of IRE1α/XBP1 in regulating dentinogenesis, tooth eruption and bone mass.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
ZHOU, YUQIAOyuz80@pitt.eduyuz80
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairShaffer, John R.john.r.shaffer@pitt.edu
Committee MemberOuyang, Hongjiaoouyang@tamhsc.edu
Committee MemberMarazita, Mary L.marazita@pitt.edu
Committee MemberMooney, Mark P.mpm4@pitt.edu
Committee MemberBeniash, Eliaebeniash@pitt.edu
Date: 12 December 2018
Date Type: Publication
Defense Date: 13 November 2018
Approval Date: 12 December 2018
Submission Date: 4 December 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 114
Institution: University of Pittsburgh
Schools and Programs: School of Dental Medicine > Dental Science
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Dentinogenesis;Tooth eruption;Dental caries;Bone;ER stress signaling; IRE1; XBP1
Date Deposited: 12 Dec 2018 19:21
Last Modified: 12 Dec 2018 19:21
URI: http://d-scholarship.pitt.edu/id/eprint/35697

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