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Browsing by Author "Harrington, Emily"
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Item 3D Assessment of Nasopharyngeal and Craniofacial Phenotypes in Ts65Dn Down Syndrome Mice Treated with a Dyrk1a Inhibitor(2014-04-11) Starbuck, John M.; Harrington, Emily; Kula, Katherine S.; Ghoneima, Ahmed A.; Roper, Randall J.Background: Down syndrome (DS) originates from having three copies of chromosome 21 (i.e. Trisomy 21). DS is associated with many detrimental phenotypes including intellectual disabilities, heart defects, abnormal craniofacial development, and obstructive sleep apnea, which develops from restricted nasopharyngeal airways and an underdeveloped mandible. Ts65Dn mice are trisomic for about half of the orthologs on human chromosome 21 and display many phenotypes associated with DS including craniofacial abnormalities. Dyrk1a is found in three copies in Ts65Dn mice and individuals with DS, and thought to be a root cause of the craniofacial phenotypes. Epigallocatechin 3-gallate (EGCG) is a green tea polyphenol and inhibitor of Dyrk1a activity. Purpose: We hypothesize that decreased Dyrk1a activity in Ts65Dn mice will ameliorate craniofacial dysmorphology. Methods: To test our hypothesis we compared Ts65Dn mice with two or three copies of Dyrk1a and compared Ts65Dn mice with and without prenatal EGCG treatment. EGCG treated mothers were fed 200mg/kg EGCG on gestational day 7. Six week old mice were sacrificed and their heads imaged using micro-computed tomography (μCT). From μCT images, we measured nasopharyngeal airway volume and anatomical landmarks (n = 54) from the facial skeleton, cranial vault, cranial base, and mandible. Mean nasopharyngeal airway volumes were graphically compared, and a landmark-based multivariate geometric morphometric approach known as Euclidean Distance Matrix Analysis (EDMA) was carried out to assess local differences in craniofacial morphology between trisomic mouse samples. Results: Our preliminary results indicate that EGCG treatment and reduced Dyrk1a copy number increases mean nasopharyngeal airway volume in Ts65Dn mice. Craniofacial morphometric differences were found among all samples. EGCG treatment increased portions of the mandible and decreased portions of the cranial vault and cranial base. Conclusion: Preliminary analyses suggest that both EGCG treatment and reduced Dyrk1a copy number affect craniofacial morphology.Item Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome(Oxford Academic, 2016-11-15) McElyea, Samantha D.; Starbuck, John M.; Tumbleson-Brink, Danika M.; Harrington, Emily; Blazek, Joshua D.; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J.; Biology, School of ScienceTrisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene–phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.