Molecular Mechanisms of Ectopic Bone Formation

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DESCRIPTION (provided by applicant): Osteoporosis is a public health problem that affects approximately 25 million people in the United States. Regardless of the etiology, osteoporosis is characterized by an imbalance in bone remodeling. Bone remodeling involves coordinated interaction between osteoblasts and osteoclasts. Information about mechanisms of bone formation may lead to new insights into the development of strategies to induce bone formation in diseases in which bone mass is low such as osteoporosis. Patients with Albrights Hereditary Osteodystrophy (AHO) and progressive osseous heteroplasia (POH), despite differences in other clinical features, form ectopic bone. Patients with AHO and POH also have heterozygous germline GNASI mutations of the gene encoding the alpha chain of the Gs G protein. These G proteins in turn regulate activity of intracellular signal effectors, most notable of which is adenylyl cyclase, the enzyme that synthesizes the second messenger cAMP. The mechanisms by which cAMP affects bone development and or remodeling are incompletely understood, but likely involve control of gene expression. The basis for the distinct differences in the clinical features and variable phenotypes of patients with similar inactivating GNASI mutations remains unclear as well. Understanding the heterogeneity in patients with GNASI mutations might allow more precise determination of the mechanisms of bone formation. Specifically, efforts are proposed to: 1) Assess genotype/ phenotype correlations in patients with ectopic bone forination. 2) Determine whether the mosaic distribution of ectopic ossification in patients with AHO and POH reflects the acquisition of a somatic clonal mutation, in the wild type Gscc allele. 3) Reduce the expression of Gs(X in human mesenchymal cells and observe the effects on bone formation of these altered levels. 4) Examine separate candidate genes and their products to explain the somatic mosaicism of the ectopic bone. 5) Examine microarray patterns of gene expression from bone and other tissues from patients with AHO and POH. This award might afford the opportunity to gain added experience and knowledge necessary to become an independent investigator by increasing protected time in the laboratory. In the future I would like to mentor other students or junior faculty memjbers like myself and perpetuate the unique and exciting and exciting perspective clinicla and basic science training bring to scientific to scientific investigation.