# Towards a Mechanistic Undestanding of Adolscent Idiopathic Scoliosis

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $333,971

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10168460
- **Project number:** 5R01AR072009-05
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Ryan Scott Gray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,971
- **Award type:** 5
- **Project period:** 2017-07-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168460

## Citation

> US National Institutes of Health, RePORTER application 10168460, Towards a Mechanistic Undestanding of Adolscent Idiopathic Scoliosis (5R01AR072009-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10168460. Licensed CC0.

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