Systems Genetics of Bone Regeneration

骨再生的系统遗传学

• 批准号: 10464597
• 负责人: Charles R Farber
• 金额: $ 70.3万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10464597
• 关键词: Ablation; Academic Medical Centers; Address; Affect; Animal Model; 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; Enrollment; Event; Excision; Femur; Fracture; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genotype; Heritability; Impaired healing; Impaired health; In Vitro; Inflammation; Injury; Knock-out; Knockout Mice; Knowledge; Lead; 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; 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; mouse model; new therapeutic target; novel; osteogenic; periostin; repaired; sample fixation; single-cell RNA sequencing; skeletal; societal costs; targeted treatment; therapeutic target; tomography; trait; transcriptomics

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： 在美国，每年有超过100万例骨修复失败的病例，导致大量的患者死亡。 发病率和社会成本。影响骨修复的遗传因素知之甚少，因为该领域 由于必须依赖于询问与骨质疏松症或其他已知相关性的基因， 生物学过程，如炎症。这些研究只发现了少数几个基因。与此相反， 包括骨骼特征如骨矿物质密度在内的许多表型的系统遗传学研究， 已经确定了多种新的遗传变异，可以作为治疗干预的目标。 不幸的是，患者骨修复的研究不容易接受这种方法，因为 在索引事件发生后，难以将患者招募到研究中，损伤类型的变异性很大 缺乏简单的读数来评估修复情况。这些障碍可以通过使用模式生物来克服， 一个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膜内骨再生的新基因 在小鼠模型中进行消融。膜内骨修复是骨折愈合、牵引 骨生成、将矫形和牙科植入物固定到骨骼上以及修复 创伤或骨肿瘤切除所必需的。在目标1中，我们将执行第一个全基因组 通过测量膜内骨再生反应进行骨修复的相关研究（GWAS） 在骨髓消融后在Diversity Outbred（N=1000）小鼠中。我们将找出负责骨骼的基因 再生数量性状基因座（QTL）和表达QTL，使用多种精细作图方法， 从单细胞RNA-seq产生的转录组学数据。在目标2中，我们将使用贝叶斯网络并识别 基因高度连接到已知的调控骨性状使用关键驱动分析，以确定候选人 骨骼再生反应的致病基因。在目标3中，我们将验证Periostin的作用， 在前两个目标中鉴定的候选基因和至少一个另外的候选基因。我们将开始 测试Periostin的作用，Periostin是一种与膜内骨再生有关的基因， 转录组学、谱系追踪和关键驱动分析。该项目将大大提高我们的 了解骨骼修复的遗传学我们发现的基因将作为潜在的治疗靶点 能够改善依赖于骨修复的多种整形外科和牙科手术。