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Human Genetics and Clinical Translation

人类遗传学和临床转化

基本信息

批准号：
10458400
负责人：
CAROL A WISE
金额：
$ 35.7万
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 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458400
关键词：
ATAC-seq Adolescent Adult Affect Alleles Award Back Pain Biological Biological Response Modifier Therapy CRISPR/Cas technology Candidate Disease Gene Cartilage Cells Child Childhood Collagen Type XI Connective Tissue Coupled Databases Deformity Development Diagnosis Early Diagnosis Embryo Engineering Epiphysial cartilage Ethylnitrosourea Etiology Extended Family Extracellular Matrix Family Female Functional disorder Genes Genetic Recombination Genetic Screening Genetic Translation Genetically Engineered Mouse Genomics Goals Growth Health Histologic Human Human Genetics Idiopathic scoliosis Image Immunohistochemistry Intervention Intervertebral disc structure Knock-in Knock-in Mouse Knockout Mice LacZ Genes Life MMP14 gene Matrix Metalloproteinases Mechanics Medical Meta-Analysis Modeling Molecular Monitor Morphology Mus Musculoskeletal Diseases Mutation Operative Surgical Procedures Pathogenesis Pathway interactions Patients Phenotype Physiological Prevention Preventive Resistance Reverse engineering Risk Risk Factors Role School-Age Population Sex Bias Spinal Susceptibility Gene Testing Time Tissues Untranslated RNA Variant Vertebral column Zebrafish biobank bone quality boys clinical translation cohort cost experimental study gene discovery genetic architecture genome sequencing genome wide association study girls high risk multi-ethnic mutant novel offspring postnatal programs risk variant scoliosis sex sexual dimorphism single-cell RNA sequencing skeletal skeletal disorder spatiotemporal tool transcriptomics whole genome

项目摘要

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 2 and Genomics Project 3 in further defining pathways and developmental mechanisms of spine development and deformity. Our collaborative will also continue to define the genetic architecture of AIS and yield tools that will enable better diagnosis, interventions, and preventions.

项目总结