Developing therapies for rare genetic diseases is as important as for more common disorders because many of these patients are suffering from lifelong debilitating and life-threatening symptoms with treatment being limited or non-existent. The key for developing therapeutic interventions is to understand the cellular and molecular consequences of genomic abnormalities identified in these diseases. This proposal aims to identify pathogenic mechanisms of craniometaphyseal dysplasia (CMD), characterized by thickened craniofacial bones and widened metaphyses of long bones. The onset of CMD begins early in infancy and cranifacial bones progressively thicken throughout life, which can result in life-threatening consequences for patients. The obstruction of nerves by narrowing cranial foramina often leads to blindness, deafness, facial paralysis and severe headache even in young children. To date, there is no treatment for CMD other than repetitive and risky surgeries. We have generated a mouse model carrying a CMD mutation and human induced pluripotent stem cells (hiPSCs) from CMD patients and healthy donors. Cell-autonomous defects in osteoblasts and osteoclasts (OCs) in a mouse model for CMD have been reported. OCs are significantly smaller and functioanlly deficient in CMD mice and CMD patients. We use OCs to study unique mutational effects because OCs show the most notable differences between CMD mice and mice that have no ANK protein. To gain insight into how mutations in the progressive ankylosis gene ANKH (human) and ANK (mouse orthologue) cause CMD, three Specific Aims are proposed to test the central hypothesis that mutations in ANKH cause CMD by reducing levels of functional ANKH and by decreasing Ca2+/CaM signaling, which results in defective actomyosin complexes.
Aim 1 will determine the mechanisms regulating expression and localization of CMD mutant ANK/ANKH.
Aim 2 will determine the role of CMD mutant ANK on calcium signaling in osteoclasts.
Aim 3 will identify the mechanisms leading to defective actomyosin complexes in CMD osteoclasts. Findings from this project will be the basis for a future translational study to focus on developing therapeutic interventions for CMD. This project is expected to have a high impact on investigations of similar rare genetic bone disorders as well as on a better understanding of unrecognized roles of ANK/ANKH in normal bone development and beyond.

Public Health Relevance

The proposed project is relevant to public health because it will identify unrecognized pathogenic mechanisms of craniometaphyseal dysplasia (CMD) in order to develop therapeutic interventions for this lifelong debilitating craniotubular disease. The methods established in this project will also facilitate research on other rare genetic bone disorders (more than 500 identified) or more common bone diseases, like osteoporosis.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Wan, Jason
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University of Connecticut
Schools of Dentistry/Oral Hygn
United States
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