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Modeling Human Skeletal Disorders in Animals
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Modeling human craniofacial disorders in laboratory animals
Elona Kolpakova HartDepartment of Developmental Biology
Town Meeting10/21/2009
Creation of New Knowledge
Promotion of New Knowledge
Development of Analytical skills
EDUCATION PROCESS
Institutional Research in Medical and Dental Education
Potential involvement of kinesin-2 in the Oral-Facial-Digital syndrome
Cleft lip/palate defects in OFD patients and kinesin-2 knockout mouse model
kinesin-2 KO control OFD syndrome
OFD – Oral-Facial-Digital syndrome
Oral cavity defects in OFD patients and kinesin-2 knockout mouse model
tongue
mandible (lower jaw)
OFD syndrome kinesin-2 KO mouse
control kinesin-2 KO
Tongue abnormalities observed in patients with OFD and kinesin 2-
deficient mice
OFD patient kinesin-2 knockout mouse
Extra-digits found in OFD patients and kinesin-2 model mouse
OFD syndrome kinesin-2 knockout normal mouse mouse
Translating knowledge into diagnostics and treatments
Identification of a candidate gene involved in a humansyndrome/disease
Detection of causative mutation(s) in the candidate genein collaboration with patients and medical professionals
Development of diagnostic tests and potential treatments
The role of Polycystinsin human skeletal development
Impaired postnatal growth of the rostrum in the Polycystin-1 and Polycystin-2 KO mice
Cranial base defects in polycystin-1 and polycystin-2 knockout mice
control polycystin-2 KO
control polycystin-2 KO
Skull Abnormalities in Metaphyseal Chondrodysplasia Type Jansen
There are similarities between skull defects in polycystin-deficient mice and patients with Jansen’s Metaphyseal chondroplasia
Holthusen W. et al., Pediatric Radiology, 1975
Long Bone Defects in Metaphyseal Chondrodysplasia Type Jansens
• Delayed irregular ossification• Generalized symmetric shortening of long bones• Deeply-cupped metaphyseal ends of long bones• Ossified shafts of long bones
control polycystin-2 KO
Increased trabecular bone volume and bone marrow fibrosis in Jansen’s chondrodysplasia mouse model and polycystin-2 deficient mice
control Jansen’s control Jansen’s
Calvi L.M. et al, JCI, 2001
control polycystin-2 knockout control polycystin-2
knockout
Working Hypothesis
Parathyroid Hormone- and Polycystin-mediated regulatory pathways interact in regulating bone formation and growth
What is the molecular mechanism? New Genes = New Potential Drug Targets
Modeling orthodontic proceduresin animals
New bone formation in response to mid-palatal suture expansion in mice
Control Experiment
old bone new bone
Hou et al., Polycystic kidney disease 1 (Pkd1) gene is required for the responses of osteochondroprogenitor cells to midpalatal suture expansion in mice. 2009, Bone
Harvard Medical School Harvard School of Dental Medicine
Jing Zhou, BWHNicolas Brady, HSPHJoe Gleeson, UCSD
Kimberly WuKimberly Whippy
Vikrum NandaBo Hou
Bjorn R. Olsen Lab