Identification of Novel Genes Impacting Osteoblast Activity

影响成骨细胞活性的新基因的鉴定

• 批准号: 10312427
• 负责人: Cheryl Lynne Ackert-Bicknell
• 金额: $ 71.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312427
• 关键词: ATAC-seq; Affect; Age; Alleles; Anabolic Agents; Bayesian Analysis; Bayesian Network; Bone Density; Bone Diseases; Bone Matrix; Bone Resorption; Bone remodeling; Calvaria; Cells; Child; Chromosome Mapping; Collaborations; Complex; Complex Genetic Trait; Cytokinesis; Data; Development; Disease; Dissection; Drug Targeting; Ensure; Equilibrium; Extracellular Matrix; FDA approved; Fracture; Fright; Genes; Genetic; Genetic study; Goals; Heritability; Hip Fractures; Human Genetics; In Vitro; Incidence; Lead; Maps; Measures; Mediating; Minerals; Mus; Mutant Strains Mice; Network-based; Osteoblasts; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Osteoporotic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiologic calcification; Physiological Processes; Pilot Projects; Population; Prevention therapy; Process; Quantitative Trait Loci; Resolution; Risk; Role; Site; Testing; Therapeutic; Time; Trauma; Work; base; bone; bone loss; bone mass; bone strength; causal variant; cell type; common treatment; effective therapy; follow-up; fragility fracture; genetic analysis; genome wide association study; insight; migration; mineralization; neonate; new therapeutic target; novel; osteoblast proliferation; osteoporosis with pathological fracture; prevent; public health relevance; side effect; single-cell RNA sequencing; therapeutic target; trait

PROJECT SUMMARY/ABSTRACT Osteoporosis can be defined as the progressive loss of bone mass and strength with age, leading to increased risk of fragility fracture. Osteoporotic fracture and fracture-related traits, such as bone mineral density (BMD), are highly heritable and Genome-wide association studies (GWAS) for BMD have identified over 1100 associations for the phenotype of BMD. Further, there are many mono-allelic conditions, such as osteogenesis imperfecta, that lead to low BMD and low-trauma fractures in children. Bone is in a constant state of remodeling, with formation mediated by the osteoblast and resorption by the osteoclast and when these processes remain balanced, there is no net change in BMD. Imbalances in remodeling results in the loss of bone seen in osteoporosis, but a GWAS done for BMD cannot determine which of these physiological processes are affected by each locus. All current fracture prevention therapies focus on tipping the remodeling balance away from bone loss. There are three bone anabolic therapies approved by the FDA, but each of these has black box warnings, each can only be used for a limited time (1 to 2 years respectively) and none of them can be used in children. We have shown in previous work that bone mineralization by the osteoblast is a highly heritable, complex genetic trait and that genetic mapping for the absolute amount of mineralization possible yields information that is complementary to that identified by GWAS for BMD. However, the osteoblast is a highly regulated, complex cell that undergoes an as of yet incompletely described differentiation process, must be able to migrate to the site of bone remodeling, must be able to produce the proteinaceous extracellular matrix of bone and then must be able to execute mineralization. The goal of this application is to identify the key genes and pathways that control these aspects of osteoblastogensis and osteoblast function. In Aim 1, we will map high-resolution quantitative trait loci (QTL) for osteoblast maturation, migration and rate of mineral apposition. In Aim 2, we will use cutting edge Bayesian network analyses based on single cell RNA seq and single cell ATAC seq to define master control genes of various stages of osteoblast development. In Aim 3 we conduct functional follow up on genes found via our preliminary analyses that control the late stages of osteoblast function. We expect that this comprehensive and complementary approach to identify key genes for osteoblastic processes will provide critical insight into how bone is formed by the osteoblast. More importantly, the genes that we identify will serve as potential therapeutic targets capable of increasing bone formation in the setting of osteoporosis and in other formation disorders.

项目摘要/摘要 骨质疏松症可以定义为随着年龄的增长而导致骨骼质量和强度的逐渐丧失，导致增加 脆性骨折的风险。骨质疏松性裂缝和骨折相关性状，例如骨矿物质密度（BMD）， BMD的高度可遗传和全基因组关联研究（GWAS）已确定超过1100 BMD表型的关联。此外，有许多单相关条件，例如成骨 Imperfecta，导致儿童的BMD低和低创伤性骨折。骨头处于恒定状态 重塑，由成骨细胞介导并通过破骨细胞吸收以及何时介导 过程保持平衡，BMD没有净变化。重塑的不平衡导致损失 在骨质疏松症中看到的骨头，但是为BMD做的GWA无法确定这些生理 过程受每个基因座的影响。当前所有预防骨折疗法都集中于小费重塑 远离骨质流失。 FDA批准了三种骨合成代谢疗法，但每一个 这些都有黑匣子警告，每个警告只能在有限的时间内（分别为1到2年），没有 它们可以用于儿童。我们在先前的工作中表明，成骨细胞矿化是一个 高度可遗传的，复杂的遗传特征和绝对矿化量的遗传图 可能产生的信息是与GWAS确定的BMD识别的信息。但是，成骨细胞 是一个高度调节的复杂细胞，经历了尚未完全描述的分化过程， 必须能够迁移到骨骼重塑的部位，必须能够产生蛋白质外细胞外 骨骼矩阵，然后必须能够执行矿化。此应用程序的目的是确定 控制成骨细胞的这些方面和成骨细胞功能的关键基因和途径。在AIM 1中，我们 将绘制高分辨率定量性状基因座（QTL）的成骨细胞成熟，迁移和速率 申请。在AIM 2中，我们将根据单细胞RNA SEQ和 单细胞ATAC SEQ定义成骨细胞发育的各个阶段的主控制基因。在目标3中我们 通过我们的初步分析，对控制的基因进行功能随访，以控制 成骨细胞功能。我们期望这种识别关键基因的全面和互补的方法 成骨细胞过程将为成骨细胞形成骨骼的形成方式提供关键的见解。更重要的是， 我们识别的基因将作为能够增加骨形成的潜在治疗靶标 骨质疏松症和其他形成障碍的设置。