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Causal Genes at BMD Loci

BMD 位点的因果基因

基本信息

批准号：
10415241
负责人：
Ronald Y Kwon
金额：
$ 3.25万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415241
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

项目摘要

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.

项目概要/摘要骨质疏松症是一种常见的慢性疾病，给健康带来巨大负担。迫切需要新的合成代谢疗法。该项目的长期目标是了解骨质疏松症的遗传风险因素确定新的药物靶点以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，致病基因这些位点仍有待发现。该项目的基本原理是，定义 BMD 位点的因果基因是目前，这是一个表型限制的问题。更具体地说，大多数因果基因位于基因组区域侧翼 BMD 基因座。因此，每个基因座暗示存在于这些侧翼区域的多个候选基因。然而，有数百个此类候选基因的骨骼功能未知，并且在体内具有足够通量来填补这一表型空白的方法实际上是不存在的。有紧急情况科学需要了解 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，以及将这些位点转化为临床的能力目标。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骨质量的 BMD 位点基因及其机制行为。我们的中心假设是遗传变异通过调节 BMD 相关位点的基因来影响 BMD，它们协同作用影响骨量和质量。在具体目标 1 (SA1) 中，我们将识别位于以下位置的基因：反向遗传筛选中具有成人功能丧失骨骼表型的 BMD 位点。我们的团队已经确定大规模 GWAS 荟萃分析中的 56 个 BMD 位点。将采用一种新颖的表型分析策略对位于这 56 个 BMD 位点 80kb 内的候选基因进行功能注释。人类基因分析将进行探索我们筛选中识别的每个基因如何影响 BMD。在具体目标 2 (SA2) 中，我们将进行多层次的检查，以确定基因在细胞和分子机制中的作用 7q31.31 影响骨量和质量。 SA2将作为SA1中发现的新基因的模型，以及它们之间的相互作用，将被机械地评估。这个项目之所以具有创新性是因为它与 BMD 位点因果基因功能测试的现状有很大不同——使用小鼠表型分析联盟——并利用我们团队开发的方法来执行最迄今为止对 BMD 位点基因的全面功能分析。该项目意义重大，因为它将：1) 建立一个有效的模型来探索骨质疏松症相关特征的人类基因组学，为此有紧急需要； 2）在BMD基因座上识别新的骨骼基因，这是一个富含已知的骨质疏松症药物靶点，并且已被证明可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，作为模型如何不同遗传变异及其致病基因可以协同作用影响骨密度。