Identification of Novel Genes Impacting Osteoblast Activity

项目概要/摘要 骨质疏松症可以定义为随着年龄的增长，骨量和强度逐渐丧失，导致骨密度增加。 脆性骨折风险。骨质疏松性骨折和骨质疏松相关特征，如骨矿物质密度（BMD）， 具有高度遗传性，BMD的全基因组关联研究（GWAS）已经确定了超过1100种 BMD表型的相关性。此外，还有许多单等位基因条件，例如成骨 导致儿童骨密度低和低创伤性骨折。骨骼处于一种恒定的 重塑，由成骨细胞介导的形成和破骨细胞的再吸收，当这些 过程保持平衡，BMD没有净变化。重塑的不平衡导致了 骨质疏松症中所见的骨，但对BMD进行的GWAS无法确定这些生理因素中的哪一个 每个过程都受到每个位点的影响。目前所有的骨折预防疗法都集中在使重塑 避免骨质流失。FDA批准了三种骨合成代谢疗法，但每一种都是 这些都有黑框警告，每个只能在有限的时间内使用（分别为1至2年）， 它们可以用于儿童。我们在以前的工作中已经表明，成骨细胞的骨矿化是一种 高遗传复杂遗传性状与绝对矿化量遗传作图 可能产生的信息是补充GWAS确定的BMD。然而，成骨细胞 是一种高度调节的复杂细胞，其经历了迄今尚未完全描述的分化过程， 必须能够迁移到骨重建的部位，必须能够产生蛋白质样的细胞外 然后必须能够执行矿化。此应用程序的目标是识别 控制成骨细胞生成和成骨细胞功能的关键基因和途径。目标1： 将绘制成骨细胞成熟、迁移和矿物质代谢率的高分辨率数量性状基因座（QTL）， 并置在目标2中，我们将使用基于单细胞RNA序列的最先进贝叶斯网络分析， 单细胞ATAC测序以确定成骨细胞发育的各个阶段的主控基因。在目标3中， 对通过我们的初步分析发现的控制晚期阶段的基因进行功能性随访， 成骨细胞功能我们希望这种全面和互补的方法，以确定关键基因， 成骨细胞过程将为骨是如何由成骨细胞形成提供关键的见解。更重要的是， 我们发现的基因将作为潜在的治疗靶点，能够增加骨形成， 骨质疏松症和其他形成障碍的设置。

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.