Systems Genetics of Bone Regeneration

骨再生的系统遗传学

• 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
• 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

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.

项目总结： 在美国，每年有100多万例骨修复失败，导致大量患者 发病率和社会成本。影响骨修复的遗传因素知之甚少，因为这一领域 由于不得不依靠询问与骨质疏松症或其他已知相关的基因而受到限制 生物过程，如炎症。这些研究只确定了少数几个基因。相比之下， 对许多表型的系统遗传学研究，包括骨骼性状，如骨密度 已经确定了可以作为治疗干预目标的多种新的遗传变异。 不幸的是，对患者骨修复的研究并不容易接受这种方法，因为 指标事件发生后很难将患者纳入研究，损伤类型差异很大 而且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型有机体和 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 消融在小鼠模型上。膜内骨修复是骨折愈合、牵张不可缺少的 成骨，骨科和牙科植入物对骨骼的固定，以及修复由 创伤的或因切除骨肿瘤而必需的。在目标1中，我们将执行第一个全基因组 膜内骨再生反应与骨修复的相关性研究 不同杂交系(N=1000)小鼠骨髓消融后。我们将确定与骨骼有关的基因 利用多种精细定位方法获得再生数量性状基因座和表达QTL 单细胞RNA序列产生的转录数据。在目标2中，我们将使用贝叶斯网络并确定 利用关键驱动因素分析确定与已知骨骼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，这是最近的一种 确定的候选基因，以及在前两个目标中确定的至少一个额外的候选基因。我们将从 初步检测膜内骨再生相关基因Periostin的作用 转录、血统追踪和关键驱动因素分析。该项目将大大增加我们的 了解骨修复的遗传学。我们确定的基因将成为潜在的治疗靶点 能够改进依赖于骨修复的多种矫形和牙科程序。