Project 1: The pathologic process and mechanism of syndromic and non-syndromic Craniosynostosis

Craniosynostosis, which occurs one in 2500 live births, is found in over one hundred syndromes or non-syndromic conditions. It is the most common skull defect in newborns characterized by premature fusion of one or more cranial sutures, leading to craniofacial deformities and a number of other medical complications including hearing loss, cleft palate and vision impairment. Earlier investigations have revealed that various mutations in fibroblast growth factor receptor (FGFR) 1, 2 and 3 genes are responsible for a significant portion of syndromic craniosyostosis cases with potential involvement of environment-gene interactions. Utilizing genetically modified in vivo models, this project aims at delineation of FGFR-mediated signaling pathways and downstream effectors that are responsible for premature ossification of cranial sutures. We are also currently investigating the contribution of environmental factors on both syndromic and non-syndromic craniosynostosis.

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Project 2: The role of a novel gene ANKH in craniofacial bone modeling and remodeling

Autosomal dominant craniometaphyseal dysplasia is a rare genetic bone modeling disorder caused by mutations in the progressive ankylosis gene ANKH. Clinical phenotype includes excessive bone deposition along the craniofacial skeleton, leading to facial deformities and associated complications including facial paralysis, blindness, and hearing loss due to cranial nerve compression from skeletal overgrowth into the nerve canals. ANKH is a cell membrane protein highly conserved in vertebrates and has been suggested to be involved in the transport of inorganic pyrophosphate and bone mineralization. Modulation of ANKH activity could potentially serve as an effective therapeutic means for a wide spectrum of disorders with excessive or deficient mineralization of tissues. Our focus in this study is to identify specific roles and mechanisms of pyrophosphate and ANKH in the regulation of bone modeling and remodeling during normal and abnormal development using in vivo and in vitro genetic approaches.

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Project 3: A genome-wide association (GWA) study for orofacial clefting

Clefts of the lip and palate (CL/P) affect about 1/1000 births with wide variability related to geographic origin and socioeconomic status, and are a source of substantial morbidity and mortality worldwide. Etiology of CL/P is multifactorial, consisting of both genetic and environmental components. Combining the recruitment of a large phenotyped cohort of individuals with orofacial clefts from the Cleft Lip and Palate Clinic at the Children's Hospital of Philadelphia, with the recent developments in high throughput genome-wide SNP genotyping, this collaborative project with the Center for Applied Genomics aims to study genes and genetic variants that influence orofacial clefting in children by conducting a genome-wide association (GWA) study using a high density tag-SNP platform. This study will also target investigation of gene-gene and gene-environment interactions.

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Project 4: In utero somatic gene delivery in the modelled rescue of cleft palate.

Recent successes of in utero gene transfer in several disease models include the treatment of Crigler Najjar disease, restoration of vision in Leber's Congenital Amaurosis (a form of congenital blindness), prevention of Pompe's disease, and amelioration of hemophilia B and α-thalassemia, demonstrating its worth as a therapeutic modality and highlighting its future potential. These studies establish that in utero gene delivery can provide a significant phenotypic correction sufficient to reduce or prevent the devastating consequences of genetic disease. Currently, gene therapy has not been applied to any craniofacial disorder leading us to hypothesize that it may be applied to a genetic model of Cleft Palate; thus, intervening in the disease process at the onset of altered palatal development to preempt the severe manifestation of deformities and associated complications. Utilizing a well-characterized genetic and non-genetic disease model for cleft palate, we are studying the rescue potential and mechanisms of intra-amniotic delivery of the TGF-β3 gene in palatal development. The scope of this project will be broadened as we learn more about the genetic birth defects that can be targeted with in utero therapy.

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Project 5: Development of a 3-D printed regenerative bone scaffold for craniofacial reconstruction

The repair of large bony defects resulting from congenital defects, trauma, or tumor resection remains to be a major challenge in pediatric craniofacial reconstructive surgeries due to a lack of suitable bone substitutes. Current surgical procedures commonly involve the use of autografts, allografts or polymeric and metallic implants, which have numerous limitations including: donor site morbidity, shortage of donor tissue supply, poor integration with surrounding host tissue, host rejection, potential disease transmission and bacterial colonization. The regenerative property of a bone substitute is particularly critical for pediatric patients, since non-regenerative materials used in tissue reconstruction need to be repeatedly replaced to keep up with the changes in surrounding structures in the growing child. New and improved polymers with promising potential for bone tissue engineering applications are becoming increasingly available. However, viability of bone depends on nutrients and oxygen delivered by blood vessels; thus, angiogenesis (the creation of blood vessels) is an essential pre-requisite for 3-D scaffold-guided reconstruction of large bone volume. Through collaborations with investigators in the Bioengineering School of University of Pennsylvania and Engineering School of Drexel University, we are working on development of a regenerative 3-D bone scaffold for pediatric craniofacial reconstruction.

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Project 6: Wound Healing

Impaired wound healing (e.g. traumatic wounds in diabetics, necrotizing soft tissue infections, burns, etc.) is a significant source of morbidity and healthcare expenditure. Maggot therapy, using live maggots, was once widely used in treating chronic wounds during World War I and II; however, it soon fell out of favor with the introduction of antibiotics. With increasing bacterial resistance to antibiotics and current limited approaches to chronic wounds, we decided to revisit the benefits of maggot therapy. Recent data suggests that maggots secretions are found to contain proteinases that degrade extracellular matrix and promote the migration of fibroblasts in vitro, which may play a role in wound healing in addition to having antibacterial properties. However, there has been no in vivo study of these wound healing effects. Therefore, this project is designed to evaluate the efficacy of maggot excretion/secretion in improving wound healing in a diabetic model known to have impaired wound healing. Should wound healing be improved, future studies will be directed to isolate specific components needed for wound healing.

Funding Sources:

NIH/NIAMS, Department of Defense, American Association of Plastic Surgeons, ACPA, AAMS, Mary Downs Endowment Fund

American Society of Maxillofacial Surgeons and Plastic Surgery Educational Foundation

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Hyun-Duck Nah, DMD, PhD
Hyun-Duck Nah, DMD, PhD
Research Director
Craniofacial Research Laboratory
Plastic and Reconstructive Surgery
Children's Hospital of Philadelphia
Lab. Phone: 267-426-5563
Email Address: CraniofacialResearch