My NIH-funded research is centered on inherited connective tissue disorders, in particular the Ehlers Danlos syndrome, a group of collagen-related diseases that affects skin and joints. I have researched and published extensively on the autosomal recessive kyphoscoliotic form of the Ehlers Danlos syndrome and the causative mutations in the lysyl hydroxylase1 gene (LH1), an important post-translational modifying enzyme in collagen biosynthesis. A deficiency of this enzyme disrupts the collagen cross-linking that is crucial for the tensile strength of collagen, a major component of skin and bone. My laboratory conducts a diagnostic assay for this enzyme deficiency that is used to confirm the clinical diagnosis. Where indicated, mutational analysis and prenatal diagnosis can also be performed.
Major projects include characterization of the family of lysyl hydroxylases (LH1, LH2 and its alternatively–spliced form, and LH3) by kinetic and structure/function analysis in a baculovirus expression system; analysis of the pattern of collagen hydroxylation (telopeptide versus helical domains) and collagen crosslinking by the individual baculovirally-expressed lysyl hydroxylases; and analysis of LH isoforms in normal and diseased matrix.
We are currently studying the alternate splicing mechanism of lysyl hydroxylase 2 (LH2) which exists in two alternatively spliced forms; the major form is the long transcript with the inclusion of a 63bp exon that is spliced out in the short form. These transcripts appear to have specificity for hydroxylation of lysines in the telopeptide and helical collagen domains, respectively. As LH2(long) is over-expressed in fibrotic cells with a corresponding increase in collagen telopeptide-related pyridinoline collagen cross-links, one of our goals is to define the regulatory factors affecting the splicing pathway, using a functional minigene. Analysis of the factors controlling the splicing pattern may offer potential sites for therapeutic intervention in fibrotic conditions such as scleroderma.
I am on the Editorial Board for the Journal of Investigative Dermatology. At Duke University, I am a Senior Fellow of the Center for the Study of Aging and Development, a member of the RNA Faculty and the Duke Comprehensive Cancer Center.
I have successfully mentored several medical students in my laboratory, 2 of whom received Howard Hughes Fellowships, another received a Loo Stead Fellowship, 2 were John Hartford Foundation Fellows (NIH), and 2 were American Dermatology Association Fellows. They now have successful medical careers in Dermatology, Pediatrics, Opthalmology, ENT and OB-GYN. I am on the PhD committees of 2 students at UNC, Chapel Hill and I have served as Opponent on a final PhD examination of a student thesis at Oulu University in Finland. I also review PhD theses from other Finnish doctoral students on a regular basis.
Connective tissue disease, collagen biosynthesis, dermal fibroblasts, collagen crosslinking, lysyl hydroxylase (LH), expression and regulation of LH isoforms, Ehlers Danlos syndrome type VI, mutational analysis, baculovirus expression systems.