Craniosynostosis is a disorder whose mechanism has been long sought after and whose therapies have remained elusive. The overwhelming bulk of mechanistic and therapeutic data and literature focus on molecular regulation of osteoblasts and related signaling pathways. Few investigations have targeted the role of osteoclasts and biomechanical regulation of osteoblasts and osteoclasts within the cranial suture. Recent studies in our lab have also demonstrated the importance of mechanical stimuli in governing cranial suture patency and closure. Our proposal herein is novel in the sense that we intend to unveil the role of the osteoclast in suture homeostasis in the context of physiological biomechanical forces in the suture microenvironment. We are also developing unique ex vivo biomechanical reactors and cell-actuators with a collaborator at UIC to treat craniosynostotic sutures and cranial defects. Such information will not only bolster our understanding of the biomechanical and downstream biochemical cues that regulate suture fate, but also lead to the development of cutting-edge therapies that can address dysregulated suture growth and re-synostosis.

1) To identify established and novel molecular factors that govern suture patency and suture fusion from an osteoclastic perspective.

2) To create a human craniomaxillofacial suture database via proteomic, genomic and morphometric analysis.

3) To identify molecular markers that may be specific to suture type (cranial vs. facial) and patency status. Such determinations will confirm our hypothesis that discrete, activated genes and proteins, determine normal morphology and growth at a particular suture/region of the face, whereas imbalances of such genes and proteins contribute to sutural dysmorphology, abnormal facial growth and facial pathology.

Human suture samples obtained from patients who have undergone surgery for craniosynostosis from a collaborator (UCSD) will be inventoried, banked and processed for RNA. RNA-sequencing will be used to capture differentially expressing genes (DEGs) comparing to control (patent) sutures. These DEGs will then be used to manipulate mouse models in both craniosynostotic and surgical animal models.

Huggins Conference; Plastic Surgery Research Council.