Bone Regenerative Strategies Targeting the Notch Pathway

Emory University

Shelly Abramowicz, DMD, MPH
Dr. Abramowicz provides care to children with oral and maxillofacial surgery concerns. Her clinical and research specialties include pediatric oral and maxillofacial surgery, TMJ dysfunction in children with juvenile idiopathic arthritis, orthognathic surgery, maxillofacial trauma, benign maxillofacial pathology, and impacted teeth.

Dr. Abramowicz obtained her dental degree and her MPH in 2002 from the University of Pittsburgh, and completed her oral and maxillofacial surgery residency at the University of Florida in 2008. After completing her training, she joined Boston Children’s Hospital and the Harvard School of Dental Medicine. She joined Emory in 2013.

She is an active researcher with a focus on the biological behavior and natural history of congenital and developmental facial deformities in children. While still at HSDM in 2009, Dr. Abramowicz received a three-year Faculty Educator Development Award from the American Association of Oral and Maxillofacial Surgeons and the American Oral and Maxillofacial Surgery Foundation. The award funded her investigation of temporomandibular joints in children with juvenile idiopathic arthritis. In 2016, she received a research support grant from the American Oral and Maxillofacial Surgery Foundation, was a first place poster winner at the 98th Annual Meeting of the American Association of Oral and Maxillofacial Surgeons, and was the first recipient of the Elaine A. Stuebner Scholarship from the American College of Oral and Maxillofacial Surgeons. In 2018, she was awarded an Osteo Science Foundation Research Grant to study bone regenerative strategies targeting the notch pathway.

Steven L. Goudy, MD
Dr. Steven Goudy is the Director of Pediatric Otolaryngology at Emory University where he has a laboratory focused on craniofacial bone development and regeneration.  Working closely with Dr. Shelly Abramowicz, Associate Professor of Oral Surgery at Emory, they focus on developing regenerative approaches to pediatric craniofacial bone loss using animal models.

Using in vitro and in vivo approaches, Drs. Goudy and Abramowicz are developing innovative approaches for drug and cell delivery, leveraging their collaborations with the Georgia Institute of Technology.  

Abstract:

The current options for bone grafting in adults include autologous bone graft harvest, donated autogenous bone, and bone regeneration using growth factor delivery, primarily using Bone Morphogenetic Protein 2 (BMP2).  Options for bone grafting in children are limited due to concerns about use of donor bone and lack of FDA approval of BMP2 use in children. The development of a regenerative strategy to replace and/or repair bone loss in children is critically needed to reduce cost and morbidity.

Delivery of Bone Morphogenetic Protein 2 (BMP2) using a collagen sponge has successfully regenerated bone in adults to treat facial bone loss and during cervical spine fusion. BMP2 is not FDA-approved for the treatment of children due to the off target effects of BMP2, including life-threatening swelling and inflammation. Delivery of growth factors and cells requires that the delivery vehicle has moderate term permanence, avoids significant host tissue inflammation, and is easily cleared from the host. Many investigators are pursuing multiple pathways to identify additional genes, growth factors and cells that can be targeted for bone regeneration.  

This proposal focuses on the Notch signaling pathway as a potential target to regenerate bone without inducing significant inflammation.  Our lab has demonstrated the requirement of Jagged1, a cell surface ligand in the Notch pathway, during craniofacial bone formation and we have created a mouse model of maxillary bone loss. Jagged1 is a cell surface ligand in the Notch gene family that is necessary in determining cell fate. Human mutation of JAGGED1 leads to Alagille syndrome, characterized by cardiac, and bony phenotypes. Taken together these findings indicate that Jagged1 plays an important role in bone development, and interruption of Jagged1 function is associated with obvious clinical manifestations of bony loss and targeted Jagged1-therapies may provide another therapeutic option for bone regeneration in children.