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Center for Craniofacial Innovation Research Overview
The Center for Craniofacial Innovation integrates the approaches of classical developmental and modern stem cell biology and use these to explore human tissue regeneration and disease. Below are highlights of our currents research projects.
Genome sequencing technology continues to advance with ever increasing speed and efficiency and decreased cost. It is now possible to obtain genomic sequencing data in clinical time frame even during the prenatal period. However, the exponential and accelerated growth of genomic data has only exacerbated and underscores the difficulty in translating this data to clinically actionable information.
For example, whether it is somatic sequencing data from tumors or germline sequencing data from congenital conditions, resolving the sequence information down to a causative gene has for the most part defied computational tools, often requiring experimental evidence to impute pathogenicity. Further, newer systems and tools need to be developed to handle the integration and analysis of genomic data.
Vertebrate Craniofacial Morphogenesis
Formation of the vertebrate facial structures requires coordination of complex molecular and morphogenetic cues. The genes regulating facial development are well conserved across vertebrate species, where minor molecular variations contribute to dramatic alterations in form.
We take advantage of the versatility of forward and reverse genetics in zebrafish as a model to assay function of human cleft candidate genes and demonstrated that the zebrafish palate (ethmoid plate) is morphogenetically homologous to the mammalian primary palate.
We also showed that convergence and extension mechanisms operate in palate morphogenesis, and we are dissecting the Wnt pathway genetically.
Advances in clinical treatment of congenital craniofacial malformations require improved understanding of the developmental genetic basis of facial morphogenesis. Our goal is to investigate fundamental genetic regulation of facial development with a focus on translating basic science discoveries to clinical treatments.
Dougherty M, Kamel G, Grimaldi M, Gfrerer L, Shubinets V, Ethier R, Hickey G, Cornell RA, Liao EC. Distinct requirements for wnt9a and irf6 in extension and integration mechanisms during zebrafish palate morphogenesis. Development. 2013 Jan 1;140(1):76-81. PMID: 23154410
Rochard L, Monica SD, Ling IT, Kong Y, Roberson S, Harland R, Halpern M, Liao EC. Roles of Wnt pathway genes wls, wnt9a, wnt5b, frzb and gpc4 in regulating convergent-extension during zebrafish palate morphogenesis. Development. 2016 Jul 15;143(14):2541-7. PMID: 27287801
Kamel G, Hoyos T, Rochard L, Dougherty M, Kong Y, Tse W, Shubinets V, Grimaldi M, Liao EC. Requirement for frzb and fzd7a in cranial neural crest convergence and extension mechanisms during zebrafish palate and jaw morphogenesis. Dev Biol. 2013 Sep 15;381(2):423-33. PMID: 23806211
Functional Genomics Pipeline
We are applying zebrafish to carry out high throughput functional genomics studies, to characterize human genes implicated in orofacial clefts. We are also using zebrafish as the biological platform to identify chemicals that specifically regulate craniofacial morphogenesis, or even discover compounds that mitigate malformations.
With continued revolutionary advance in human gene sequencing approaches, there is a pressing need to bridge the gap between whole genome analysis and clinical use of this data. Determination of pathogenicity of human gene variants is a major challenge in the field, limiting clinical usefulness of whole genome sequencing information. We apply functional assays in iPSC and zebrafish models toward functional analysis of human gene variants associated with cleft and craniofacial anomalies.
Mukherjee K, et al. Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis. Hum Mol Genet. 2016 Apr 1;25(7):1255-70. PMID: 26758871
Gfrerer L, Shubinets V, Hoyos T, Kong Y, Nguyen C, Pietschmann P, Morton CC, Maas RL, Liao EC. Functional analysis of SPECC1L in craniofacial development and oblique facial cleft pathogenesis. Plast Reconstr Surg. 2014 Oct;134(4):748-759. PMID: 25357034
Kong Y, Grimaldi M, Curtin E, Dougherty M, Kaufman C, White RM, Zon LI, Liao EC. Neural crest development and craniofacial morphogenesis is coordinated by nitric oxide and histone acetylation. Chem Biol. 2014 Apr 24;21(4):488-501. PMID: 24684905
Li EB, Truong D, Hallett, SA, Mukherjee K, Schutte BC, Liao EC. Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model. PLoS Genet. 2017 Sep 25;13(9): e1007009. PMID: 28945736
We consider multi-omics in a broad sense to mean integration of large datasets (e.g., genomic sequencing, RNA sequencing, proteomics, deep phenotyping, and clinical outcomes) to reveal new insight or actionable information to drive scientific or clinical advances. For craniofacial conditions, we are interested in integrating morphometric data, clinical functional data, and molecular diagnosis, as intersection of data across independent approaches increases the significance and robustness of discovery.
Advances in gene editing and gene delivery are critical technology enablers of gene therapy applications now revolutionizing medicine and offering hope to patients living with conditions such as sickle cell disease, leukemia, and diabetes. We are developing gene therapy tools to improve treatment of craniofacial conditions. As craniofacial surgeons, we are developing innovative biomaterials and devices for use in surgical procedures to replace or enhance bone and soft tissue.
Patients inspire our research. The CHOP clinical craniofacial program is one of the most robust in the world, with regional, national, and international referral of high volume and high complexity craniofacial conditions. There is a longstanding history of contribution from CHOP and Penn on treatment of craniosynostosis, cleft lip and palate, and other craniofacial conditions.
We are engaged in many clinical outcomes studies to refine surgical procedures, improve safety and patient experience, and initiate first-in-child clinical trials in order to advance craniofacial care for children and their families. Wherever possible, we reach out to patient groups to enhance patient advocacy and feedback.