Integrative Biology and Infectious Diseases Branch
Division of Extramural Research
OBJECTIVE
This comprehensive research initiative is focused on understanding the genetic basis of craniofacial construction and the development of craniofacial diseases and disorders. The accumulated knowledge will be housed in a database termed “FaceBase”; the “FaceBase Project”, begun under this initiative, embraces the elements of experimental data collection and annotation, data coordination and integration, systems level analyses, and clinical application. The long-term program goal is to accelerate development of molecular medicine for improved risk assessment, effective prevention, screening and treatment strategies, as well as functional restoration in oral, dental and craniofacial disorders.
We propose to implement the FaceBase Project by supporting consortia of collaborative research projects each comprising a multidisciplinary team sharing a common research focus, and targeting their studies at specific aspects of craniofacial development (e.g., cranial neural crest migration, formation of lip and palate, cranial sutures, tooth, salivary gland or temporomandibular joint) and associated clinical conditions. It is envisioned that a consortium will propose new research projects for funding consideration but may also include existing funded projects that are consistent with the FaceBase theme. Two central resources will serve the consortia and will comprise: 1) a data coordination and bioinformatics component; and 2) a technology development component. Integration of these resources with the FaceBase consortia will foster high-throughput, genome-wide research strategies as well as the application of new technologies for identifying key genes regulatory pathways controlling craniofacial construction.
The consortia will be tasked with the efficient and rapid generation of new data resources and the execution of research strategies to test hypotheses. Projects could include the development of structural and molecular atlases of development, detailed comparative analyses across model organisms or between wild type and genetic or environmental mutants, genome-wide association and linkage studies, polymorphism mapping, synthesis of gene regulatory networks, or modeling of cellular processes across stages of development. Taken together, these collaborative projects will provide a comprehensive knowledge base for a systems-level understanding of normal and abnormal craniofacial development. This is critical for tackling the challenge of treatment and prevention of complex disorders affecting craniofacial and dental tissues. Each FaceBase consortium will also nurture the next generation of craniofacial scientists, either within the consortium itself, or as an interactive activity with existing training programs.
The data coordination and bioinformatics component will serve as a centralized hub to provide data management, integration, and analysis for the consortia and craniofacial community at large. It will import data from consortium studies, integrate with existing datasets, implement standardized data format and, importantly, develop a publicly accessible web-based user-minable resource for the deposition of verified data. This component will be accessible for multi-scale analysis of craniofacial data derived from biochemical, molecular, genetic and morphological studies, ranging from single genes to networks. This includes temporal and spatial patterning information underlying craniofacial morphogenesis and dysmorphogenesis in humans and model systems. This hub will facilitate data sharing and the development of informatics tools that evolve with time as the data become more complex. In particular, the web-based resource will provide an informatics platform to provide access to large datasets, facilitating analysis, dissemination of experimental results, fostering interactions and collaborations within the research consortia and the research community at large.
The technology development component will pursue innovative technologies essential for understanding craniofacial construction; e.g. high resolution imaging of developmental processes in vivo, development of markers and probes to track normal and abnormal developmental processes at the single cell level, high-throughput screening methods for structural and functional alterations, algorithms for 4-D expression and co-expression pattern analysis, computational modeling of gene regulatory networks, and novel gene silencing technologies.
Armed with the human genome and high-resolution information on sequence variations, coupled with increasingly powerful technologies to analyze genomic information and gene expression profiles, we are at the next frontier of using molecular information to understand human craniofacial development and diseases at a systems level. We have the opportunity to build upon this foundation of high-density genomic data to unravel, at a systems biology level, the genetic, epigenetic and environmental factors that produce complex diseases. The FaceBase Project research consortia and the two supporting central resources will provide our research communities with the tools to achieve a comprehensive understanding of craniofacial construction and enhance our ability to investigate, diagnose and ameliorate human craniofacial diseases and disorders. By understanding the complex regulatory networks that govern normal craniofacial morphogenesis and the variations that contribute to diseases and disorders, we can begin to face the future with predictive, preemptive and personalized medicine.
BACKGROUND
More than half of all birth defects are associated with some form of craniofacial malformation. Orofacial clefts alone occur in approximately one in 700 live births, and affect more than 6,800 infants every year in the United States. Although surgery can correct these structural defects, patients still face a lifetime of functional, social, and aesthetic challenges. Many other syndromes are associated with oral, dental and craniofacial defects, and although less common than clefts, these syndromes exert a tremendous financial, social and psychological burden on affected families. One of the key missions articulated in the NIDCR Strategic Plan is to strive through research, to build a broader knowledge base for the development of methods to prevent craniofacial birth defects, and to improve prenatal diagnosis and treatment. In addition, one of our top research priorities in the Implementation Plan for the Strategic Plan is to advance the understanding of the normal and abnormal processes underlying oral, dental and craniofacial diseases and disorders by supporting research to understand the molecular mechanisms underlying gene-disease associations, genes, and gene products in normal craniofacial development, and gene-environment interactions in oral, dental and craniofacial diseases and disorders.
While there have been successes in identifying and characterizing the genetic etiology of many craniofacial disorders with ‘simple’ Mendelian inheritance, much less is known regarding the genetics of complex disease traits and the extent of environmental perturbation. It is increasingly evident that cumulative small effects of numerous alleles and variations in gene dosage may confer predisposition to diseases, including susceptibility to infection. Differences in penetrance and expressivity of genetic variants highlight the importance of genetic background and environmental exposures in determining complex disease phenotypes. Moreover, it is becoming apparent even for Mendelian traits, that much research is needed to achieve a molecular and cellular understanding of the mechanisms by which genes and gene products interact to generate complex phenotypes.
In recent years developmental biologists have made tremendous progress in revealing conserved gene regulatory modules that are crucial for patterning the cranial neural crest and signaling pathways that regulate tissue interactions during craniofacial development. Human geneticists have also achieved remarkable recent success in identifying genes involved in craniofacial defects. For example, genes recently shown to play a role in human cleft lip and palate include the IRF6 gene, FGF and FGFR families, the FOXE1 gene and the BMP4 gene. These genes have largely been revealed in genome-wide linkage scans and SNP analysis of candidate genes run on global populations. These successes have positioned us to tackle the next challenge, that of achieving a comprehensive systems biology understanding of how collections of genes interact at the cellular level, to generate normal or defective complex craniofacial phenotypes. This craniofacial construction research theme seeks to approach this goal by establishing multidisciplinary research consortia that merge expertise and integrate information on genetic, cellular, and systems levels to achieve mechanistic insights that will support the design of efficient interventions.
The NIDCR portfolio currently supports a broad spectrum of individual research projects on normal and abnormal craniofacial development that are primarily focused on the function of single genes or specific signaling pathways in mouse, avian, zebrafish, and other model systems. Few projects support multidisciplinary collaborations that merge genetics, developmental biology, and modeling expertise and are aimed at achieving a systems biology comprehensive understanding of the mechanisms that underlie complex craniofacial phenotypes. Nevertheless, these activities have seeded the necessary components such that a deliberate effort to integrate them into the FaceBase consortia is timely and would allow them to synergize.