Identification of Novel Genes Impacting Osteoblast Activity

影响成骨细胞活性的新基因的鉴定

基本信息

批准号：
10649471
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 68.35万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10649471
关键词：
ATAC-seq Affect Age 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 Equilibrium Extracellular Matrix FDA approved Fracture Fright Genes Genetic Genetic study Goals Heritability Hip Fractures Human Genetics In Vitro Incidence 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 Proliferating Quantitative Trait Loci Resolution Risk Role Site Testing Therapeutic Time Trauma Work bone bone loss bone mass bone strength candidate identification causal variant cell type common treatment effective therapy follow-up fragility fracture genetic analysis genome wide association study genome-wide analysis 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 translational potential

项目摘要

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.

项目概要/摘要骨质疏松症可以定义为随着年龄的增长，骨量和骨强度逐渐丧失，导致骨密度增加。脆性骨折的风险。骨质疏松性骨折和骨折相关特征，例如骨矿物质密度 (BMD)、具有高度遗传性，BMD 的全基因组关联研究 (GWAS) 已确定超过 1100 BMD 表型的关联。此外，还有许多单等位基因条件，例如成骨作用不完美，导致儿童骨密度低和创伤性低的骨折。骨骼处于恒定状态重塑，由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，BMD 没有净变化。重塑过程中的不平衡会导致骨质疏松症中出现的骨骼，但针对 BMD 进行的 GWAS 无法确定这些生理学中的哪一个过程受到每个位点的影响。目前所有的骨折预防疗法都侧重于重塑骨折平衡远离骨质流失。 FDA 批准了三种骨合成代谢疗法，但每一种都这些都有黑框警告，每个只能使用有限的时间（分别为 1 到 2 年），并且没有一个它们可以用于儿童。我们在之前的工作中已经表明，成骨细胞的骨矿化是一种高度遗传、复杂的遗传性状以及矿化绝对量的遗传图谱可能产生的信息与 GWAS 确定的 BMD 信息相补充。然而，成骨细胞是一种高度调控的复杂细胞，其分化过程尚未完全描述，必须能够迁移到骨重建部位，必须能够产生蛋白质细胞外骨基质然后必须能够进行矿化。该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这些方面的关键基因和途径。在目标 1 中，我们将绘制成骨细胞成熟、迁移和矿物质比率的高分辨率数量性状位点 (QTL) 对位。在目标 2 中，我们将使用基于单细胞 RNA seq 的尖端贝叶斯网络分析和单细胞 ATAC seq 定义成骨细胞发育各个阶段的主控基因。在目标 3 中，我们对通过我们的初步分析发现的控制后期阶段的基因进行功能跟踪成骨细胞功能。我们期望这种全面且互补的方法能够识别关键基因成骨细胞过程将为成骨细胞如何形成骨骼提供重要的见解。更重要的是，我们确定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情况。