Developmental Mechanisms of Human Idiopathic Scoliosis

人类特发性脊柱侧凸的发育机制

• 批准号: 10646372
• 负责人: Nadav Ahituv
• 金额: $ 135.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646372
• 关键词: ATAC-seq; Address; Adolescent; Adult; Affect; Alleles; Animal Model; Automobile Driving; Award; Back Pain; Biological Assay; Biological Response Modifier Therapy; CRISPR/Cas technology; Cartilage; Cells; Child; Childhood; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Sequence Alteration; Data; Deformity; Development; Diagnosis; Disease; Disease model; Elements; Engineering; Enhancers; Epigenetic Process; Ethylnitrosourea; Etiology; Extracellular Matrix; Family; Female; Female Adolescents; Fiber; Fishes; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genetic Transcription; Genetic study; Genetically Engineered Mouse; Genomic Segment; Genomics; Hospital Charges; Human; Human Genetics; Idiopathic scoliosis; Impairment; Induced Mutation; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Life; Link; MMP14 gene; Maps; Medical; Modeling; Molecular; Monitor; Mus; Musculoskeletal Diseases; Mutation; Names; Nature; Pain; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Predisposition; Preventive; Procedures; Productivity; Refractory; Regulation; Regulator Genes; Regulatory Element; Resources; Risk; Role; School-Age Population; Sex Distribution; Signal Transduction; Specificity; Spinal; Spinal Diseases; Susceptibility Gene; System; Tail; Testing; Therapeutic Studies; Tissues; Untranslated RNA; Variant; Vertebral column; Work; Zebrafish; boys; candidate validation; cohort; collaborative approach; data integration; exome sequencing; experimental study; forward genetics; gene discovery; genetic architecture; genome editing; genome wide association study; girls; high risk; human model; human tissue; innovation; knowledge integration; male; mouse model; mutant; nonsynonymous mutation; novel; null mutation; postnatal; prevent; programs; reverse genetics; risk variant; scoliosis; sexual dimorphism; single-cell RNA sequencing; somitogenesis; therapeutic target; tool; transcriptomics

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 AIS in patients refractory to treatment. We will also expand our investigations to address why AIS has a female bias, and to testing rationally selected drug therapies in vertebrate models. These studies will advance fundamental understanding of AIS, inform diagnosis and highlight potential therapeutic targets.

项目摘要/摘要（总体）

项目成果

CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

• DOI: 10.1371/journal.pone.0189591
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Einarsdottir E;Grauers A;Wang J;Jiao H;Escher SA;Danielsson A;Simony A;Andersen M;Christensen SB;Åkesson K;Kou I;Khanshour AM;Ohlin A;Wise C;Ikegawa S;Kere J;Gerdhem P
• 通讯作者: Gerdhem P

Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study.

• DOI: 10.1002/jbm4.10830
• 发表时间: 2023-12
• 期刊: JBMR plus
• 影响因子: 3.8

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

• DOI: 10.3389/fendo.2023.1089414
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2

Impaired glycine neurotransmission causes adolescent idiopathic scoliosis.

• DOI: 10.1172/jci168783
• 发表时间: 2024-01-16
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Wang, Xiaolu;Yue, Ming;Cheung, Jason Pui Yin;Cheung, Prudence Wing Hang;Fan, Yanhui;Wu, Meicheng;Wang, Xiaojun;Zhao, Sen;Khanshour, Anas M.;Rios, Jonathan J.;Chen, Zheyi;Wang, Xiwei;Tu, Wenwei;Chan, Danny;Yuan, Qiuju;Qin, Dajiang;Qiu, Guixing;Wu, Zhihong;Zhang, Terry Jianguo;Ikegawa, Shiro;Wu, Nan;Wise, Carol A.;Hu, Yong;Luk, Keith Dip Kei;Song, You-Qiang;Guo, Bo
• 通讯作者: Guo, Bo

Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality.

Pax1 脊柱侧凸相关调节元件的缺失会导致女性偏向的尾部异常。

• DOI: 10.1101/2023.04.12.536497
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ushiki,Aki;Sheng,RoryR;Zhang,Yichi;Zhao,Jingjing;Nobuhara,Mai;Murray,Elizabeth;Ruan,Xin;Rios,JonathanJ;Wise,CarolA;Ahituv,Nadav
• 通讯作者: Ahituv,Nadav