Towards a Mechanistic Undestanding of Adolscent Idiopathic Scoliosis

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Project Summary: Here we seek to understand the cellular and molecular causes of a common pediatric musculoskeletal disease, adolescent idiopathic scoliosis (AIS). Human population studies of AIS are beginning to uncover important risk loci for this disease, but there has been limited progress in understanding the etiology of AIS. In part, this is due to a lack of good, genetically tractable animal models of scoliotic diseases. We will focus our efforts on the functional analysis of a few explicit animal models of AIS which we generated in both mouse and zebrafish model systems. At the same time, we will advance gene discovery in this field, by applying modern genetic approaches to characterize novel mutations that cause AIS-like spine deformity in an existing collection of zebrafish mutants we generated. The project will test the following hypotheses: First, that late-onset scoliosis in our Gpr126 mouse model is a consequence of embryonic defects of the intervertebral discs. Second, that functional analysis of Gpr126 signaling in cartilage and the intervertebral disc will provide a mechanistic understanding of the pathophysiology of AIS in humans, as well as, help to emphasize new genes and pathways that contribute to AIS. Third, that our plan for gene discovery in the zebrafish model and functional analysis of AIS-like scoliosis in zebrafish and mouse models will provide a synergistic framework for more mechanistic understanding of the causes of AIS in humans. These hypotheses will be tested under three Specific Aims: I. Determine when and where Gpr126 is required for AIS. Loss of Gpr126 function in a common progenitor cell of cartilage and bone tissues models AIS in the mouse. Using conditional genetic approaches in the mouse, we will refine how the loss of Gpr126 in these tissues contribute to the onset and progression of scoliosis and we will define the temporal window for Gpr126 function in spine development. II. What is the molecular function of Gpr126 in the intervertebral disc and cartilage? Here we will investigate the mechanism by which Gpr126 controls the maturation and deposition of the cartialge extracellular matrix and the development of the interverterbal disc and how this relates to onset of scoliosis in the mouse. III. Characterization of the molecular genetics and etiologies of spine deformity. To identify genes and pathways important for normal spine development, we utilized a forward genetics approach to isolate a collection of adult-viable spine deformity mutant zebrafish. We will apply massively parallel sequencing to identify novel spine deformity disease genes in these existing mutant lines. In order to gain a mechanistic understanding of scoliosis we will: a) undertake functional analysis of two of these novel mutant zebrafish lines, affecting extracellular matrix modifying genes; and b) investigate the etiology of scoliosis in an explicit zebrafish model of a well-known human AIS risk locus. The results are excepted to reveal previously unknown mechanisms and pathways essential for normal spine development.