# Human Genetics and Clinical Translation > **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $318,245 ## Abstract Project Summary Adolescent idiopathic scoliosis (AIS) is a twisting condition of the spine and is the most common pediatric musculoskeletal disorder, affecting 3% of children worldwide. Children with AIS risk severe disfigurement, back pain, and physiologic dysfunction later in life, and are treated symptomatically rather than preventively because the underlying etiology is unknown. Girls requiring treatment for AIS outnumber boys by more than five-fold. Our overall purpose is to understand the biologic causes of AIS as a means to early diagnosis, prevention and non- invasive biologic treatment. With support from this P01 in the previous award period we substantially increased the number of validatedAIS susceptibility loci by large-scale multi-ethnic GWAS meta-analysis. Together with the other projects in the program we also established that the cartilage extracellular matrix (ECM) is a functional tissue in AIS. We subsequently discovered that nonsynonymous variants in genes encoding ECM components COL11A1 and MMP14 are associated with AIS. Together with genomics Project 3 we uncovered evidence of sex-biased PAX1-COL11A1 expression. In parallel, whole genome sequencing in families identified candidate mutations in AIS families that zebrafish Project 2 is engineering into orthologous zebrafish genes. Here we propose to drive these discoveries forward to develop mechanistic understanding of AIS pathogenesis. In one aim of the project, we will evaluate the consequences of Col11a1 loss from chondrogenic lineages by generating Col11a1fl/fl /ATC Cre lines, inducing cre recombination at embryologic and at early postnatal timepoints. Mutant offspring and their littermates will be evaluated phenotypically and morphologically, by imaging, quantitative immunohistochemistry and mechanical strength testing of growth plate and intervertebral disc (IVD) cartilages. With Project 3-Genomics we will also perform single cell RNAseq coupled with ATAC-seq in IVD to define the role of Col11a1 at cellular levels. To characterize the role of Mmp14 in mouse spine, we will characterize its spatio-temporal expression, and its cell-specific role in spine development using MT1-MMPlacZ/+ knockin lines. In a second aim, we will continue reverse engineering together with Project 2-Zebrafish and Project 3-Genomics to characterize the molecular and functional consequences of spine deformity-associated mutations in vertebrate models. In a reciprocal fashion we will cross-reference new scoliosis candidate alleles identified in Project 2-Zebrafish or Project 3-Genomics with those identified in our human cohorts. In a third aim we will discover novel high-risk scoliosis-associated variants by genome sequencing extended families and a unique cohort of AIS treatment non-responders. We will also identify new spine deformity mutants from our highly productive ENU-induced genetic screen in mice. Building on the momentum of our previous discoveries, we will synergize with Zebrafish Project... ## Key facts - **NIH application ID:** 10862694 - **Project number:** 5P01HD084387-08 - **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER - **Principal Investigator:** CAROL A WISE - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $318,245 - **Award type:** 5 - **Project period:** 2016-09-01 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10862694 ## Citation > US National Institutes of Health, RePORTER application 10862694, Human Genetics and Clinical Translation (5P01HD084387-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862694. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*