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Developmental Mechanisms of Human Idiopathic Scoliosis

人类特发性脊柱侧凸的发育机制

基本信息

批准号：
9974349
负责人：
Nadav Ahituv
金额：
$ 112.36万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974349
关键词：
Address Adolescent Affect Animal Model Back Pain Biological Biological Assay Biological Models Biological Response Modifier Therapy CRISPR/Cas technology Candidate Disease Gene Cartilage ChIP-seq Chemicals Child Childhood Clinical Clinical Research Complex Coupled Data Set Deformity Development Disease Disease model Early Diagnosis Encyclopedias Engineering Enhancers Etiology Family member Functional disorder Future Gene Expression Gene Mutation Genes Genetic Genetic Diseases Genetic Screening Genomics Goals Haplotypes Heritability Heterogeneity Hospital Charges Human Idiopathic scoliosis Induced Mutation Infection Investigation Kinesin Knowledge Lead Life Life Style Literature Lung Malignant Neoplasms Massive Parallel Sequencing Medical Methods Modeling Modernization Molecular Molecular Diagnosis Musculoskeletal Diseases Mutation Names Nucleic Acid Regulatory Sequences Obesity Pain Pathogenesis Pathway interactions Patients Pattern Pharmacologic Substance Phenotype Play Population Positioning Attribute Predisposition Prevention Prevention therapy Preventive Procedures Reagent Regulation Regulatory Element Research Research Personnel Risk School-Age Population Solid Spinal Structural defect System Testing Time Tissues Untranslated RNA Validation Variant Vertebral column Work Zebrafish base boys causal variant cohort collaborative approach cost efficient exome gene discovery genetic architecture genome editing genome sequencing genome wide association study genomic platform girls innovation male mouse genome mutant mutational status nonsynonymous mutation novel novel therapeutics null mutation postnatal prevent proband programs sequencing platform sex spatiotemporal tool transcription activator-like effector nucleases transcriptome sequencing virtual whole genome

项目摘要

Project Summary/Abstract 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 pulmonary dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than five-fold, for reasons that are unknown. AIS is treated symptomatically rather than preventively because the underlying etiology is unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than for other pediatric procedures. Our overall purpose is to understand the biologic causes of AIS as a means to early diagnosis, prevention and non-invasive biologic treatment. Adolescent idiopathic scoliosis is a complex genetic disease. Genome wide association studies (GWAS) of common non-coding variants by our group and others have identified AIS-associated haplotypes, but the mechanistic basis of these associations remains to be defined. Furthermore these findings explain less than 5% of overall heritability due in part to the fact that the AIS exome has yet to be fully interrogated. Another barrier to understanding the pathogenesis of AIS in humans has been the lack of appropriate, genetically- defined animal models that are essential for defining spatiotemporal involvement in the disease. Finally the developmental regulation of postnatal spinal development generally, and the specific tissue of origin in AIS specifically, are poorly understood. To address these issues we have established an innovative collaborative approach combining unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and genomic analysis of postnatal spine development. Specifically, the component activities of our proposed Program will synergize to yield the tools and fundamental knowledge that the field of AIS research has lacked, addressing the following goals: (1) We will define the genetic architecture conveying AIS susceptibility as identified in human populations; (2) We will develop the first genetically tractable vertebrate system for modeling AIS and studying the functional consequences of AIS mutations identified in humans; (3) We will define cis-and trans-regulation of AIS causal genes; (4) We will pilot a large-scale genomics platform to begin to characterize the molecular mechanisms controlling spinal development; (5) We will identify and characterize causal mutations in patients that may identify gene-based AIS subtypes; (6) By filling gaps in fundamental knowledge of the disease we will drive innovative efforts to develop new therapies for AIS. Our discoveries will spur the field toward much-needed hypothesis-driven research aimed at early molecular diagnosis, prevention and therapies. We also expect that these studies will enlighten other structural defects of humans.

项目总结/文摘