Phone: (267) 426-7969
Position: Adjunct Associate Professor
Clinical Assistant Professor of Orthodontics
Temple University School of Dental medicine
The overall goal of my research program is to study the molecular regulatory mechanisms of collagen genes during normal and abnormal craniofacial skeletogenesis.
Formation of craniofacial skeleton involves complex processes. For example, although both synchondroses (primary cartilage) and sutures and articulations (secondary cartilage) undergo endochondral ossification, they have different histological and biochemical profiles and different intrinsic growth potentials. In addition, although calvarial and facial bones appear to form by intramembranous ossification without cartilagenous primordia, I and others have observed transient expression of some cartilage-characteristic collagen genes during intramembranous ossification.
Collagens are crucial structural elements which determine the physical chemical properties of cartilage and bone. In addition, the genes encoding types I, II and III collagen may have additional functions in chondrogenesis that are unrelated to their roles in production of structural proteins. We have isolated two forms of alpha 1(II) collagen mRNA produced by alternative splicing of the second exon; which encodes a cysteine-rich globular domain in the amino-propeptide. These two forms of alpha 1(II) collagen mRNA are differentially expressed during chondrogenesis. The earlist detectable isoform, type IIA, includes a cysteine-rich globular domain encoded by exon 2; this isoform is detected predominantly in prechondrogenic mesenchymal cells. Highly differentiated chondrocytes, such as those in articular cartilage, contain the isoform IIB, in which exon 2 has been spliced out. The resulting change in type II collagen isoform is believed to be a critical event in chondrocyte differentiation. Recent experiments from Dr. Adams' laboratory have demonstrated that supression of types I and III collagen synthesis in normal chondrocytes from chick embryos is mediated by an unusual transcriptional regulatory mechanism. We have identified chondrocyte-specific internal promoters in the genes encoding both 2 subunit of type I collagen and the alpha 1 subunit of type III collagen and demonstrated that transcripts initiating at those promoters cannot encode the expected collagen proteins, and may encode noncollagenous proteins; thus it may also have an alternative function in cartilage.
We will use in situ hybridization and RNAse protection assays to characterize the developing chick craniofacial skeleton in terms of the collagen mRNAs known to be important for chondrogenesis and osteogenesis, including the alternative mRNAs of the type I, II, and III collagen genes. We will compare the pattern of collagen gene expression in synchondroses (primary cartilage) and sutures and articulations (secondary cartilage) with that in the epiphyseal growth plate, which has been extensively characterized at the molecular and biochemical levels. We will also identify additional cartilage-characteristic collagen genes which are transiently expressed in differentiating calvaria (membranous bones). These experiments will permit us to further define the molecular mechanisms involved in endichondral ossification in primary and secondary cartilages and intramembranous ossification.
Based on the collective data, in near future,
we will propose the studies regarding (1) the functional roles of alternative
type I, II and III collagen transcripts during normal and abnormal development
of the craniofacial skeleton; and (2) the role of cartilage- characteristic
collagen genes in intramembranous ossification.