Thesis (M.S.)--University of Michigan, 1957.

Thesis (M.S. in oral sciences)--University of Illinois at Chicago, 1999. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. Sc.)--Dalhousie University, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. Sc.)--Dalhousie University, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Doctoral)--Bayerischen Ludwig-Maximilians-Universität zu München, 1934.

Thesis--Royal Dental College, Copenhagen, 1970. / Includes bibliographical references (p. 161-[165]).

Thesis--Royal Dental College, Copenhagen, 1970. / Includes bibliographical references (p. 161-[165]).

No description available.

The mammalian palate develops early in embryogenesis by way of a carefully orchestrated series of temporally and spatially regulated signaling events. Molecular signaling pathways that have been proven to be vital to the process of palatogenesis include TGF-βs, BMPs, FGFs, EGF, and Wnts. The absence of connective tissue growth factor (CTGF/CCN2) has been shown previously to cause failure of proper palatogenesis, i.e. cleft palate. However, the details about the phenotype of this model of cleft palate were scarce. Additionally, CCN2 is known to interact with TGF-βs, BMPs, FGFs, EGF, and Wnts, though information on how these pathways were impacted in the developing palate lacking CCN2 were also not available. In Chapters 2 and 3, through our use of gross specimen and histological examination combined with cell and organ culture, we produced the most detailed characterization of the CCN2 knockout (KO) model of cleft palate with identification of negatively affected signaling pathways that lead to the clefting phenotype. Collection and examination of gross and histological sections revealed at 100% penetrance of cleft palate in which development is impaired around the phase of palatal shelf elevation. Organ culture also revealed that when artificially apposed, the CCN2 KO model system also suffers from a fusion deficit. Finally, utilizing cells isolated from the developing palates, we found a reduction in proliferation, adhesion, and spreading with an enhanced migratory ability. Addition of recombinant CCN2 was able to rescue cell spreading but not proliferation. CCN2 as an immobilized substrate did not rescue adhesive ability. Decreased adhesion and spreading in the KO cells are attributed to the inability of the KO cells to activate Rac1 and RhoA. Examination of gene expression differences by mRNA-sequencing and qRT-PCR revealed numerous gene expression alterations between the wild type (WT) and the KO palates, most notably FGF4 and EGFR. Addition of FGF4 or EGF to cell culture was unable to promote increased proliferation in the KO cells while producing a response in the WT cells. Examination of downstream signaling revealed highly amplified and prolonged ERK1/2 signaling in the FGF4 treated palate cells indicating that FGF signaling is significantly altered in the absence of CCN2. Treatment of the cells with EGF produced a response proportional to EGFR expression differences indicating that EGFR signaling is not impacted beyond the receptor protein levels. The link between EGFR protein levels and FGF mediated ERK1/2 activation is a protein called Spry2. We found greatly reduced Spry2 mRNA levels in the KO palates and upon FGF4 stimulation at 24 hours of exposure indicating that in the absence of CCN2, proper inhibition of FGF signaling and EGFR degradation is negatively altered. Collectively, the data demonstrate that CCN2 is vital to palatogenesis by impacting proliferation, shelf elevation, and shelf fusion through increased FGF signaling and reduced EGFR signaling resulting partially from reduced Spry2 activity. / Biomedical Sciences

In mainland China, around 20,000 infants with non-syndromic cleft lip and/or palate are born every year. There is a great clinical need for the rigorous investigation of the speech problems in this population. This thesis aimed to investigate the consonant misarticulations in native Putonghua speakers with repaired cleft palate based on a research project comprised of four studies. Misarticulations associated with cleft palate are well established for English and several other Indo-European languages. However, few research articles describing the articulation of Putonghua (standard Mandarin Chinese) speakers with cleft palate have been published in English language journals. Study One reviewed relevant studies published over the past 30 years in Chinese language journals. Thirty-seven articles were analyzed and coded on a number of methodological variables. This critical review identified many methodological issues. These design flaws made it difficult to draw reliable conclusions about characteristic articulation errors. Seeing the methodological shortcomings found in Study One, a cross-sectional approach was used in Study Two to identify common consonant error patterns. Thirty-two speakers with repaired cleft palate were allocated to four groups dependent on age and the type of cleft. Articulation was evaluated based on the Putonghua Segmental Phonology Test and the Deep Test for Cleft Palate Speakers in Putonghua. The data were transcribed using International Phonetic Alphabet conventions by two experienced examiners. Several ‘language universal’ findings were identified. In addition, distinctive features in Putonghua phonology appeared to contribute to the observed language specific error patterns. The following two studies focused on the particularly vulnerable manner of articulation: affricates. The results from Study Three showed that distorted affricates from speakers with repaired cleft palate exhibited distinctive spectral features compared to typical articulation. These spectral findings added objective evidence to support the articulation deviation noted in Study Two. Study Four examined the relationship between spectral moments and perceptual judgment of accuracy for the place of affricate and to explore whether listeners relied on different spectral moments to perceive place of articulation. Both typical and distorted affricates were played to twelve listeners to make a judgment of articulation accuracy using visual analog scaling. Results showed that the third spectral moment (L3) was significantly correlated with perceptual rating of accuracy of place information from typical speakers. For affricates produced by speakers with cleft palate, the first moment (M1) showed a significantly correlation with perceptual judgment of the accuracy of alveolar affricates. Recommendations concerning methodological issues in the perceptual investigation of cleft palate speech were given in the systematic review. For the first time, the speech error study demonstrated the influence of language-specific features on Putonghua cleft palate speech. The spectral study contributed to our understanding of the differences in affricate production between speakers with cleft and their typical speaking peers. The investigation of the relationship between spectral features and the perception of alveolar and retroflex affricates provided specific clinical directions for establishing the correct place of articulation. Further research is needed to explore the contribution of other variables (e.g., age of palatoplasty) to the error patterns identified in the present study. / published_or_final_version / Speech and Hearing Sciences / Doctoral / Doctor of Philosophy