Systems Genetics of Bone Regeneration

骨再生的系统遗传学

基本信息

批准号：
10606560
负责人：
Charles R Farber
金额：
$ 69.93万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606560
关键词：
Ablation Academic Medical Centers Address Affect Bayesian Network Bilateral Biological Process Bone Density Bone Regeneration Bone neoplasms Candidate Disease Gene Cells Chicago Complex Data Defect Dental Care Dental Implants Disease Distraction Osteogenesis Event Excision Femur Fracture Genes Genetic Genetic Variation Genetic study Genome Genotype Heritability Heterozygote Impaired healing Impairment In Vitro Inflammation Injury Knock-out Knockout Mice Knowledge Maps Marrow Measures Mechanics Molecular Morbidity - disease rate Mus Network-based Orthopedic Procedures Orthopedics Osteoporosis Pathway interactions Patients Phenotype Population Public Health Quantitative Trait Loci Regenerative response Research Role Single Nucleotide Polymorphism Skeleton Stress Fractures System Testing Therapeutic Intervention Tissues Trauma Universities Virginia bone bone fracture repair bone lead bone repair candidate identification causal variant cell type common treatment design diverse data experimental study gene discovery gene network genetic analysis genetic approach genetic variant genome wide association study improved in vivo indexing innovation intramembranous bone long bone mesenchymal stromal cell model organism mouse model new therapeutic target novel osteogenic participant enrollment periostin repaired sample fixation single-cell RNA sequencing skeletal societal costs targeted treatment therapeutic target tomography trait transcriptomics

项目摘要

Project Summary: There are over 1 million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. The genetic factors affecting bone repair are poorly understood because the field has been limited by having to rely on interrogating genes with known relevance for osteoporosis or other biological processes such as inflammation. These studies have identified only a handful of genes. In contrast, systems genetics studies of many phenotypes including skeletal traits such as bone mineral density have already identified multiple novel genetic variants that can be targeted for therapeutic intervention. Unfortunately, the study of bone repair in patients is not readily amenable to this approach because of the difficulty in enrolling patients in studies after the occurrence of the index event, great variability in injury types and lack of simple readouts to assess repair. These barriers can be overcome by using a model organism with a well-defined injury mechanism and simple readout to characterize the repair phenotype. Thus, we will use systems genetics to discover novel genes influencing intramembranous bone regeneration induced by marrow ablation in a mouse model. Intramembranous bone repair is integral to fracture healing, distraction osteogenesis, fixation of orthopedic and dental implants to the skeleton and repair of large defects caused by trauma or necessitated by resection of bone tumors. In Aim 1, we will perform the first genome-wide association study (GWAS) for bone repair by measuring the intramembranous bone regenerative response after marrow ablation in Diversity Outbred (N=1000) mice. We will identify genes responsible for bone regeneration quantitative trait loci (QTL) and expression QTL using multiple fine-mapping approaches and transcriptomic data generated from single cell RNA-seq. In Aim 2, we will use Bayesian networks and identify genes highly connected to known regulators of bone traits using Key Driver Analysis to identify candidate causal genes for the bone regenerative response. In Aim 3, we will validate the role of Periostin, a recently identified candidate gene, and at least one additional candidate identified in the first two aims. We will begin by testing the role of Periostin, a gene implicated in intramembranous bone regeneration in preliminary transcriptomic, lineage tracing and key driver analyses. The project will significantly increase our understanding of the genetics of bone repair. Genes that we identify will serve as potential therapeutic targets capable of improving multiple orthopedic and dental procedures which rely on bone repair.

项目概要：美国每年有超过 100 万例骨修复失败病例，导致大量患者死亡发病率和社会成本。人们对影响骨修复的遗传因素知之甚少，因为该领域由于必须依赖于已知与骨质疏松症或其他疾病相关的基因，因此受到限制生物过程，例如炎症。这些研究只鉴定出了少数基因。相比之下，对许多表型（包括骨矿物质密度等骨骼特征）的系统遗传学研究已经已经发现了多种可用于治疗干预的新型遗传变异。不幸的是，患者骨修复的研究并不容易采用这种方法，因为指标事件发生后难以将患者纳入研究，损伤类型差异很大并且缺乏评估修复的简单读数。这些障碍可以通过使用模型生物来克服明确的损伤机制和简单的读数来表征修复表型。因此，我们将使用系统遗传学发现影响骨髓诱导的膜内骨再生的新基因小鼠模型中的消融。膜内骨修复是骨折愈合、牵引的重要组成部分成骨、将骨科和牙科植入物固定到骨骼上以及修复由以下原因引起的大缺陷外伤或因骨肿瘤切除而必需的。在目标 1 中，我们将进行首次全基因组研究通过测量膜内骨再生反应进行骨修复的关联研究（GWAS） Diversity Outbred (N=1000) 小鼠骨髓消融后。我们将鉴定负责骨骼的基因使用多种精细作图方法进行再生数量性状位点 (QTL) 和表达 QTL 从单细胞 RNA-seq 生成的转录组数据。在目标 2 中，我们将使用贝叶斯网络并识别使用关键驱动分析来识别与已知的骨性状调节因子高度相关的基因骨再生反应的因果基因。在目标 3 中，我们将验证 Periostin 的作用，Periostin 是最近的一种药物确定的候选基因，以及在前两个目标中确定的至少一个附加候选基因。我们将从初步测试 Periostin（一种与膜内骨再生有关的基因）的作用转录组学、谱系追踪和关键驱动因素分析。该项目将显着提高我们的了解骨修复的遗传学。我们确定的基因将作为潜在的治疗靶点能够改善多种依赖骨修复的骨科和牙科手术。