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.

项目摘要：每年美国有超过100万例骨骼修复失败，导致大量患者发病率和社会成本。影响骨修复的遗传因素的理解很少，因为该领域由于不得不依靠与骨质疏松症或其他相关性的询问基因的审问，受到限制生物学过程，例如炎症。这些研究仅确定了少数基因。相比之下，许多表型的系统遗传学研究，包括骨骼特征，例如骨矿物质密度已经确定了可以针对治疗干预的多种新型遗传变异。不幸的是，由于这种方法，对患者的骨修复研究不容易受到这种方法索引事件发生后，难以入学患者参加研究，伤害类型的差异很大缺乏简单的读数来评估维修。可以通过使用模型生物与定义明确的伤害机制和简单的读数，以表征修复表型。因此，我们将使用系统遗传学发现了影响骨髓诱导的膜内骨再生的新基因在鼠标模型中消融。膜内骨修复是断裂愈合不可或缺的一部分成骨，骨科和牙齿植入物对骨骼的固定以及由大缺陷的修复创伤或通过切除骨肿瘤需要。在AIM 1中，我们将执行第一个全基因组协会研究（GWAS）通过测量膜内骨再生反应来修复骨修复多样性杂种（n = 1000）小鼠的骨髓消融后。我们将确定负责骨骼的基因再生定量性状基因座（QTL）和表达QTL，使用多种细映射方法和从单细胞RNA-Seq产生的转录组数据。在AIM 2中，我们将使用贝叶斯网络并确定使用关键驱动器分析以识别候选者，高度连接到已知的骨骼性状调节因子的基因骨再生反应的因果基因。在AIM 3中，我们将验证骨膜素的作用，最近确定的候选基因，以及前两个目的中至少确定的另外一名候选人。我们将从测试骨膜素的作用，骨膜素的作用与膜内骨再生有关转录组，谱系跟踪和关键驱动程序分析。该项目将大大增加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标能够改善依赖骨修复的多种骨科和牙科手术。