# Developmental Mechanisms of Human Idiopathic Scoliosis > **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $1,427,879 ## Abstract Project Summary/Abstract (Overall) 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. Girls requiring treatment for AIS outnumber boys by more than five-fold, for reasons that are unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than for other pediatric procedures. AIS is treated symptomatically rather than preventively because the underlying etiology has been poorly understood. Genetic contributions to AIS are significant, but few human susceptibility loci were identified prior to the beginning of this Program. The mechanisms driven by these loci were likewise largely unknown, as they mapped within non-coding genomic regions that were not easily interpreted. The AIS field also lacked appropriate animal models that enable mechanistic and therapeutic studies. To address these issues, we established an innovative collaborative approach combining three Projects to lead unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and genomic analysis of postnatal spine development. Our program addressed six gaps in knowledge: (i) identity of the tissue and cellular origins of AIS; (ii) defining the true beginning of AIS disease pathogenesis; (iii) defining the genetic factors and genetic interactions underlying AIS; (iv) developing robust vertebrate systems to functionally validate, interpret, and model human genetic findings; (v) defining the molecular mechanisms controlling spinal development post-somitogenesis, and the correlation with AIS; (vi) defining the basis of sexual dimorphism in AIS. In the prior award cycle our Program significantly advanced each of these initiatives. Integrating data in humans and animal models, our data underscored cartilage as a functional tissue in AIS and specifically highlighted the extracellular matrix compartment, new paradigms in the field. Our Program discovered several new AIS genetic susceptibility loci in human and developed 73 new zebrafish models of spine deformity. Data from each Project also converged on the hypomorphic nature of AIS disease alleles, supporting multigenic inheritance. We defined the non-coding regulatory landscape of human and mouse AIS-related tissues, and discovered that knockout of one such regulator linked to female AIS in humans produces a female-biased phenotype in mouse. Here we propose a comprehensive plan to drive these discoveries forward to define AIS disease mechanisms using genetically targeted mouse and zebrafish models, to define cell-specific transcriptional, epigenetic, and signaling mechanisms underlying AIS, to continue identifying vertebrate models of spine deformity by forward genetic screens in mouse and zebrafish, and to discover new high-risk alleles contributing to... ## Key facts - **NIH application ID:** 10458398 - **Project number:** 2P01HD084387-06A1 - **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER - **Principal Investigator:** Nadav Ahituv - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $1,427,879 - **Award type:** 2 - **Project period:** 2016-09-01 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10458398 ## Citation > US National Institutes of Health, RePORTER application 10458398, Developmental Mechanisms of Human Idiopathic Scoliosis (2P01HD084387-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10458398. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*