Identification of Novel Genes Impacting Osteoblast Activity

项目摘要/摘要 骨质疏松症可以定义为随着年龄的增长，骨量和强度的进行性丧失，导致骨量和强度增加 脆性骨折的风险。骨质疏松性骨折和骨折相关特征，如骨密度(BMD)， 是高度可遗传的，全基因组范围的骨密度相关性研究(GWAS)已确定超过1100个 与骨密度表型的相关性。此外，还有许多单等位基因的情况，如成骨 不完善，导致儿童低骨密度和低创伤骨折。骨骼处于恒定的 改建，成骨细胞介导的形成和破骨细胞的吸收，当这些 过程保持平衡，骨密度没有净变化。改建的不平衡导致损失 骨质疏松症中可见骨，但骨密度检查不能确定这些生理学指标中的哪一项 过程受每个轨迹的影响。目前所有的骨折预防治疗都集中在倾倒重建。 保持平衡，避免骨质流失。FDA批准了三种骨合成代谢疗法，但每一种 这些警告都有黑盒警告，每个警告都只能在有限的时间内使用(分别为1到2年)，并且没有 它们可以用在儿童身上。我们在以前的工作中已经表明，成骨细胞的骨矿化是一种 高度可遗传、复杂遗传特征和矿化量绝对量的遗传图谱 可能产生的信息是对GWAS确定的骨密度信息的补充。然而，成骨细胞 是一种高度受调控的复杂细胞，它经历了一个尚未完全描述的分化过程， 必须能够迁移到骨重塑的部位，必须能够产生细胞外的蛋白质 骨骼的基质则必须能够执行矿化。此应用程序的目标是标识 控制成骨细胞生成和成骨细胞功能的这些方面的关键基因和途径。在目标1中，我们 将定位成骨细胞成熟、迁移和矿物质速率的高分辨率数量性状基因座(QTL) 并列。在目标2中，我们将使用基于单细胞rna序列和 单细胞ATAC序列以确定成骨细胞发育不同阶段的主控基因。在《目标3》中我们 对通过我们的初步分析发现的控制晚期的基因进行功能跟踪 成骨细胞功能。我们希望这种全面和互补的方法来确定关键基因 成骨过程将提供关键的洞察力，了解成骨细胞如何形成骨。更重要的是， 我们确定的基因将作为潜在的治疗靶点，能够促进骨形成 骨质疏松症和其他形态障碍的背景。

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.