权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish

通过全基因组测序和功能验证鉴定斑马鱼骨质疏松症基因

基本信息

批准号：
10241898
负责人：
Yi-Hsiang Hsu
金额：
$ 69.47万
依托单位：
HEBREW REHABILITATION CENTER FOR AGED
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241898
关键词：
Address Affect Alleles Animal Model Area Bioinformatics Biological Biological Process Biology Bone Density CRISPR/Cas technology Characteristics Code Complex Databases Detection Disease Dual-Energy X-Ray Absorptiometry Elderly Etiology Fracture Fright Functional disorder Genes Genetic Genetic Research Genetic Screening Genetic study Genome Genome Scan Genotype Goals Heritability Hip Fractures Human Genetics Incidence Individual Knock-out Lead Link Maps Mediating Meta-Analysis Minerals Modeling Morphology Mutation Natural regeneration Osteoporosis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiology Population Privatization Public Health Reporting Research Sampling Signal Transduction Skeletal Development Skeleton Structure System Technology Time Trans-Omics for Precision Medicine Untranslated RNA Validation Variant Zebrafish base bone mass bone metabolism causal variant density drug development drug discovery genetic association genetic information genetic variant genome sequencing genome wide association study genome-wide individual variation new therapeutic target novel novel diagnostics novel strategies novel therapeutics osteoporosis with pathological fracture personalized approach personalized therapeutic programs rare variant reverse genetics side effect skeletal trait trend virtual whole genome

项目摘要

Project Summary/Abstract Osteoporosis has become a major and growing worldwide public health burden. Due to fears of side effects, the use of osteoporosis drugs has fallen by as much as 50%. Thus, there is an unmet need to develop new drugs for osteoporosis; or to develop personalized therapeutic approaches with the ability to takes into account individual variability for each patient. Using human genetic studies to identify new druggable targets should overcome the current treatment crisis in osteoporosis. Although GWAS have been successful in discovering associated genetic variants with complex traits, more than 88% of GWAS loci are non-coding, which makes the identification of causal variants and their targeted genes a difficult challenge; thus, limits the use of human genetics information in drug discovery. To overcome these challenges and get better understanding of GWAS findings, we proposed to utilize whole genome sequencing in large well-phenotyped populations as well as the CRISPR/Cas9 gene-editing zebrafish model to identify potential causal variants and targeted genes influencing skeletal integrity. Our findings may eventually lead to new diagnostics and therapeutics of osteoporosis. We proposed three specific aims, including: 1) Fine-map previous BMD GWAS loci by existing WGS in 10,000 individuals from the Trans-Omics for Precision Medicine (TOPMed) Program to identify potential causal sequence variants (functional variants) that are responsible for GWAS signals; 2) Identify novel structural variation and novel rare sequence variants associated with BMD by performing a whole genome scan using the same 10,000 WGS samples. We will replicate findings in an additional 5,000 samples selected from the GENOMOS/GEFOS consortium; 3) Functionally characterize up to 30 genes selected from aims 1 and 2 in knockout zebrafish by CRISPR/Cas9 gene-editing systems. State-of-the-art technologies for rapid phenotyping in zebrafish will be applied to a broad range of physiologies (skeletal development, ontogenesis, and regeneration) and characteristics (bone mass accrual, morphology, and mineral density). Our proposal is fundamentally important and represents the logical next step in skeletal genetics research. The results will lead to much needed new drug development to overcome the growing treatment gap in osteoporosis.

项目总结/文摘