|The Role of Jagged1 During Maxillary Development|
|Costly and invasive corrective surgery is the only clinically available intervention to treat maxillary hypoplasia, which occurs when the upper jaw bone fails to elongate, causing an outwardly-visible sunken appearance to the mid-face. Maxillary hypoplasia occurs either due to extrinsic restriction of post-natal maxillary growth (Apert’s syndrome) or intrinsic growth deficiency (25% of cleft palate patients; Alagille syndrome). Maxillary development depends on cranial neural crest cells (CNC) migrating into the palatal mesenchyme, expanding and differentiating into bone progenitors that create the bony maxilla. Existing mouse models of maxillary hypoplasia occur due to extrinsic maxillary restriction and frequently suffer perinatal death, limiting information on post-natal maxillary development. Our recent findings indicate that Jagged1, a cell surface ligand member of the Notch pathway,|
|orchestrated maxillary development in mice by intrinsically controlling (i) proliferation and extracellular matrix production and (ii) vascular branching. Importantly JAGGED1 mutations are known to cause Alagille syndrome, which is associated with cardiac, biliary, facial and bony phenotypes. Jagged1 is required early in embryonic development and global deletion of Jagged1 leads to embryonic death at E9.5 due to cranial hemorrhage. Significantly, we found that conditional deletion of Jagged1 in the CNC (using Wnt1-Cre) led to intrinsic failure of post-natal elongation of the maxilla resulting in bony maxillary hypoplasia, characterized by poor dental occlusion, feeding difficulties and noticeable cosmetic deformities, a phenocopy of human maxillary hypoplasia. Although the combined evidence supports that Jagged1 dysfunction leads to maxillary hypoplasia, the underlying mechanism is not known and critically needed.|
|The Requirement of VEGF During Palatogenesis|
|Palate formation occurs through a complex choreography of elongation, elevation and fusion. Once fused, the palate undergoes ossification in the anterior 2/3rd’s and muscle migration into the posterior 1/3rd. This dynamic process depends on rapid cellular division, vascular invasion, and intramembranous ossification. Interruption of any of these key steps in palate development leads to cleft palate formation which occurs in 1 in 1000 live births in humans. Vascular Endothelial Growth Factor (VEGF) is a critical growth factor that is expressed during embryogenesis to create new blood vessel formation. Absence of VEGF during development leads to early embryonic demise in mice, making this critical growth factor difficult to study. Hypomorphic mutation of VEGF lead to vascular anomalies and cleft palate formation with reduced palatal elongation and bone formation. Our research efforts are focused on|
|determining the requirement of VEGF signaling during palatal development, the role of vascularization on palatal elongation, elevation and fusion, and the consequences of aberrant VEGF signaling on intramembranous ossification. We are using conditional targeted deletion of VEGF in different cell types at select time points during palatogenesis to carefully decipher the signaling requirement and consequences of VEGF.|
Clinical TrialsPhase 3 Trial of OK-432
Trial using OK-432 to treat macrocystic lymphatic malformations in children.
2008 - Present
Steven L. Goudy, MD, FACS - Principal Investigator in Phase 3
Phase 2 Trial of Celebrex use in patients with RRP
Randomized double-blinded cross over trial of the use of celebrex in patients with RRP.
2010 - Present
Steven L. Goudy, MD, FACS - Principal Investigator in Phase 2
Grant AwardsK08 Grant NIDCR K08DE017953-01A2
Irf6 is critical for craniofacial development.
08/2008 - 07/2013
07/2012 - 06/2014