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