# Expanding expertise to define map protein complexes and signaling essential for skeletal structure and growth.

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $238,500

## Abstract

ABSTRACT:
This is supplemental application of an established program to investigate the regulation of the development
and homeostasis of the spine. During the first funding period, our studies demonstrated that the gene
Adgrg6, implicated in a common human spine disorder called adolescent idiopathic scoliosis, has an
essential role in maintaining spine alignment in mice. We showed that the G-protein coupled rector Adgrg6
regulates gene expression and biomechanical properties of the intervertebral discs and dense connective
tissue of the spine. Furthermore, we demonstrated that Adgrg6 stimulates cAMP signaling regulate factors
essential for homeostasis of fibrocartilaginous tissue of the spine. Our findings suggest a new hypothesis
that stimulation of cAMP signaling can decrease the onset and severity of scoliosis caused by the
loss of Adgrg6 signaling. In addition, human genetics analysis of scoliosis identified a novel variant
located in the transcriptional activation domain of the transcription factor SOX9. Significantly, targeted
disruption of this domain of Sox9 in mice caused scoliosis and dysregulation of gene expression in
fibrocartilaginous tissues of the spine. Here, we will test the hypothesis that Adgrg6 and Sox9 are
functionally linked for regulation homeostasis and alignment of the spine.
 To add breadth to our program goals, we continued a forward genetic screen to isolate a collection of spine
disorder mutant zebrafish. We recently identified two zebrafish mutants that fail to complement a novel
thoracic scoliosis phenotype, suggesting a new pathway controlling spine morphogenesis.The characterization
of this unique thoracic scoliosis phenotype will expand our knowledge into the cellular and molecular
heterogeneity of spine disorders. Here, we will test the hypothesis that thoracic scoliosis in zebrafish is
caused by a disruption of phosphatidylinositol signaling leading to defects in notochord biogenesis.
 We will test these hypotheses via studies divided into three Specific Aims. Specific Aim 1 will deepen our
mechanistic understanding of effectors of Adgrg6 signaling in the spine and test whether stimulation of cAMP
can restore homeostasis to fibrocartilaginous tissues of the spine and halt the onset and progression of
scoliosis. Specific Aim 2 will characterize the cellular and molecular causes of scoliosis in a novel Sox9
mutant mouse and use this model to test whether genetic interactions between Adgrg6 and Sox9 variants
increase the susceptibility to scoliosis. Specific Aim 3 will characterize novel thoracic scoliosis mutant
zebrafish and test a model that phosphatidylinositol signaling is essential for notochord biogenesis and spine
morphogenesis in zebrafish. Our results will provide new insights into the molecular genetics and biological
processes necessary for the development and homeostasis of the spine. These studies may provide
fundamental insights into the biological processes and pathways associated with human skele...

## Key facts

- **NIH application ID:** 11067015
- **Project number:** 3R01AR072009-07S1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Ryan Scott Gray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $238,500
- **Award type:** 3
- **Project period:** 2017-07-10 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11067015

## Citation

> US National Institutes of Health, RePORTER application 11067015, Expanding expertise to define map protein complexes and signaling essential for skeletal structure and growth. (3R01AR072009-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11067015. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*