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Pathogenic Mechanisms of Craniometaphyseal Dysplasia

颅骨干骺端发育不良的发病机制

基本信息

批准号：
9294024
负责人：
I-Ping Chen
金额：
$ 39.88万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294024
关键词：
ATP2A2 Actomyosin Affect Alleles Ankylosis Binding Proteins Blindness Bone Development Bone Diseases Calcium Calcium Signaling Calmodulin Cell Size Cell membrane Cells Cephalic Child Complex Data Defect Diphosphates Disease Dominant-Negative Mutation Dysplasia Facial paralysis Future Genes Genetic Genomics Headache Hereditary Disease Human Impairment Investigation Knock-in Mouse Knockout Mice Life Methods Molecular Mouse Protein Mus Mutant Strains Mice Mutation Myosin Light Chains Nerve Neurologic Symptoms Obstruction Operative Surgical Procedures Orthologous Gene Osteoblasts Osteoclasts Osteoporosis Pathogenesis Pathogenicity Patients Phenotype Phosphorylation Phosphotransferases Proteins Public Health Pump Reporting Research Rho-associated kinase Role Signal Transduction Symptoms Testing Therapeutic Intervention Thinking Work autosomal dominant mutation base bone cell motility craniofacial deafness gain of function induced pluripotent stem cell infancy insight long bone loss of function mouse model mutant negative affect novel protein transport sulfated glycoprotein 2 therapeutic development therapy development trafficking translational study

项目摘要

Project Summary/Abstract 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.

项目总结/文摘