Orofacial Clefts

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dc.contributor.author El Baba, Nada
dc.date.accessioned 2022-06-16T05:59:20Z
dc.date.available 2022-06-16T05:59:20Z
dc.date.copyright 2021 en_US
dc.date.issued 2021-05-09
dc.identifier.uri http://hdl.handle.net/10725/13691
dc.description.abstract During embryogenesis, orofacial development takes place whereby cells migrate to their intended destinations to form the face of the fetus. Sometimes, cells of the palatal shelves and the lip buds do not properly migrate, leaving splits in the lip and/or palate. This can happen due to a multitude of reasons under the categories of genetic and environmental factors. We aimed to investigate the genetic and molecular basis underlying a case of non-syndromic cleft lip/palate. To do so, we extracted primary cells from a cleft patient and primary cells from a healthy individual. We were interested in looking at primary fibroblastic cells from the upper right gingiva of those individuals respectively. Through whole genome sequencing, we identified three variant genes, ARHGEF18, CUL7, and EPDR1, that we could link to the cleft phenotype. Through functional assays to test the discrepancy in the behavior of both sets of cells, we assessed proliferation, motility, adhesion, and Rho GTPase activity. We found no significant differences in the proliferative abilities of the patient-derived cells and the healthy cells. The striking difference in behavior was related to cell migration, whereby the patient-derived cells showed decreased motility, increased adhesion, and a general loss of polarity compared to the healthy cells. We found markers of focal adhesions to be heavily localized at the tail regions of patient-derived cells that could explain this behavior. We also found an increased RhoA activation in these cells which could be causative of the observed increase in focal adhesions as well as a decreased Cdc42 activation which could further explain the loss in cell polarity. Our results provide evidence that the ARHGEF18, CUL7, and EPDR1 variants could be at the root of the non-syndromic cleft lip/palate phenotype and are consistent with a dysregulation of Rho GTPase activity. en_US
dc.language.iso en en_US
dc.subject Cleft lip -- Etiology en_US
dc.subject Cleft palate -- Etiology en_US
dc.subject Face -- Abnormalities -- Genetic aspects en_US
dc.subject Rho GTPases en_US
dc.subject Cancer cells -- Proliferation en_US
dc.subject Lebanese American University -- Dissertations en_US
dc.subject Dissertations, Academic en_US
dc.title Orofacial Clefts en_US
dc.type Thesis en_US
dc.title.subtitle Rho GTPase Dysregulation in Patient-Derived Primary Cells as a Cause of Impaired Migration en_US
dc.term.submitted Spring en_US
dc.author.degree Doctor of Pharmacy en_US
dc.author.school SAS en_US
dc.author.idnumber 201601005 en_US
dc.author.commembers Georgess, Dan
dc.author.commembers Khalaf, Roy
dc.author.department Natural Sciences en_US
dc.description.physdesc 1 online resource (xiv, 41 leaves): ill. (some col.) en_US
dc.author.advisor El Sibai, Mirvat
dc.author.advisor Ghassibe Sabbagh, Michella
dc.keywords Cleft lip/palate en_US
dc.keywords Orofacial development en_US
dc.keywords Cell migration en_US
dc.keywords Cell adhesion en_US
dc.keywords Rho GTPases en_US
dc.keywords RhoA en_US
dc.keywords Cdc42 en_US
dc.keywords Focal adhesions en_US
dc.keywords Gene variants en_US
dc.description.bibliographiccitations Includes bibliographical references (leaf 37-41) en_US
dc.identifier.doi https://doi.org/10.26756/th.2022.223
dc.author.email nada.elbaba@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php en_US
dc.publisher.institution Lebanese American University en_US
dc.author.affiliation Lebanese American University en_US

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