Causal Genes at BMD Loci

BMD 位点的因果基因

• 批准号: 10163803
• 负责人: Ronald Y Kwon
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163803
• 关键词: Adult; Affect; Age; American; Biological; Biology; Bone Density; CRISPR/Cas technology; Candidate Disease Gene; Case Study; Characteristics; Chromosomes; Chronic Disease; Clinical; Clinical Markers; Data; Diagnosis; Drug Targeting; Exhibits; Gene Expression; Genes; Genetic; Genetic Screening; Genomic Segment; Goals; Health; Heritability; Hip Fractures; Human; Human Genetics; Incidence; Individual; Knowledge; Measures; Meta-Analysis; Modeling; Modification; Molecular; Morphology; Mus; Osteoblasts; Osteogenesis Imperfecta; Osteoporosis; Osteoporotic; Pathway interactions; Phenotype; Proteins; Rapid screening; Risk; Serine; Signal Transduction; Skeleton; Structure; Testing; Translating; Work; Zebrafish; base; bone; bone fragility; bone mass; bone quality; causal variant; gene discovery; gene function; genetic analysis; genetic risk factor; genetic variant; genome wide association study; genome-wide; human genomics; in vivo; innovation; loss of function; loss of function mutation; microCT; mutant; new therapeutic target; novel; reverse genetics; skeletal; trait; virtual

PROJECT SUMMARY/ABSTRACT Osteoporosis is a common, chronic disease with an enormous health burden. There is an urgent need for new anabolic therapies. The long-term goal of this project is to understand genetic risk factors for osteoporosis to identify new drug targets to reduce this massive health burden. Genome wide association studies (GWAS) have identified hundreds of loci associated with bone mineral density (BMD). However, the causal genes at these loci remain to be discovered. The rationale for this project is that defining causal genes at BMD loci is, at present, a phenotype-limited problem. More specifically, most causal genes reside in the genomic regions flanking BMD loci. Thus, each locus implicates multiple candidate genes residing in these flanking regions. However, there are 100s of such candidate genes whose skeletal functions are unknown, and in vivo approaches with sufficient throughput to fill this phenotype gap are virtually non-existent. There is an urgent scientific need to understand the functions of genes at BMD loci, because they form the basis for understanding how genetic variants influence BMD, and in turn, the ability to translate these loci into clinical targets. The objective of this project is to leverage rapid-throughput biology in zebrafish to advance our understanding of genes at BMD loci that influence bone mass and quality, and the mechanisms by which they act. Our central hypothesis is that genetic variants influence BMD by regulating genes at BMD-associated loci, which work in concert to influence bone mass and quality. In specific aim 1 (SA1), we will identify genes at BMD loci with adult loss-of-function skeletal phenotypes in a reverse genetic screen. Our team has identified 56 BMD loci in a large-scale GWAS meta-analysis. A novel phenotyping strategy will be employed to functionally annotate candidate genes residing within 80kb of these 56 BMD loci. Human genetic analyses will be performed to explore how each gene identified in our screen contributes to BMD. In specific aim 2 (SA2), we will perform a multi-level examination to determine cellular and molecular mechanisms by which genes at 7q31.31 influence bone mass and quality. SA2 will serve as a model by which new genes discovered in SA1, and their interactions with each other, will be mechanistically evaluated. This project is innovative because it substantially differs from the status quo for functional testing for causal genes at BMD loci—the use of mouse phenotyping consortiums—and harnesses approaches developed by our team to perform one of the most comprehensive functional analyses of genes at BMD loci to date. This project is significant because it will: 1) establish an efficient model for exploration of human genomics underlying osteoporosis-related traits, for which there is an urgent need; 2) identify new skeletal genes at BMD loci, a genetic territory that is enriched with known osteoporosis drug targets, and which has proven to yield drug targets likely to be clinically viable; 3) define mechanisms by which genes at 7q31.31 influence bone mass and quality, as a model of how different genetic variants and their causal genes can act in concert to affect BMD.

项目总结/摘要 骨质疏松症是一种常见的慢性疾病，对健康造成巨大负担。迫切需要 新的合成代谢疗法这个项目的长期目标是了解骨质疏松症的遗传危险因素 以确定新的药物靶点来减轻这一巨大的健康负担。全基因组关联研究（GWAS） 已经确定了数百个与骨矿物质密度（BMD）相关的位点。然而，致病基因在 这些位点仍有待发现。该项目的基本原理是，在BMD位点定义致病基因， 目前，一个表型有限的问题。更具体地说，大多数致病基因位于基因组区域， 侧接BMD位点。因此，每个基因座暗示多个候选基因驻留在这些侧翼区。 然而，有数百个这样的候选基因，其骨骼功能是未知的，并且在体内 实际上不存在具有足够通量以填补该表型缺口的方法。目前迫切 科学需要了解BMD位点基因的功能，因为它们构成了 了解遗传变异如何影响BMD，反过来，将这些基因座转化为临床应用的能力， 目标的该项目的目标是利用斑马鱼的快速通量生物学来推进我们的研究。 了解影响骨量和质量的BMD基因座基因及其机制 法我们的中心假设是遗传变异通过调节BMD相关基因座的基因来影响BMD， 它们协同作用以影响骨量和质量。在特定目标1（SA 1）中，我们将在以下位置鉴定基因： 反向遗传筛选中成人功能丧失骨骼表型的BMD位点我们的团队已经确认 大规模GWAS荟萃分析中的56个BMD位点。将采用一种新的表型分型策略， 功能性注释位于这56个BMD基因座的80 kb内的候选基因。人类基因分析将 进行，以探索如何在我们的屏幕上确定每个基因有助于骨密度。在具体目标2（SA 2）中， 我们将进行多层次的检查，以确定细胞和分子机制，基因在 7q31.31影响骨量和骨质量。SA 2将作为一个模型，通过它在SA 1中发现的新基因， 以及它们之间的相互作用，将被机械地评估。这个项目是创新的，因为它 与BMD基因座致病基因功能检测的现状--使用小鼠 表型分析联盟-并利用我们的团队开发的方法来执行一个最 迄今为止对BMD基因座的基因进行了全面的功能分析。该项目意义重大，因为它将：1） 建立了一个有效的模型，用于探索人类基因组学中与糖尿病相关的特征， 有迫切的需要; 2）确定新的骨骼基因在BMD位点，一个遗传领域，是丰富的， 已知的骨质疏松症药物靶点，并且已经证明产生可能在临床上可行的药物靶点; 3） 定义7q31.31基因影响骨量和质量的机制，作为不同骨质的模型 遗传变异和它们的致病基因可以协同作用以影响BMD。