Diversity Supplement: Talking Back: Leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication

多样性补充：回话：利用功能失调的破骨细胞来识别破骨细胞-成骨细胞通讯的新途径

• 批准号: 10518427
• 负责人: Julia F Charles
• 金额: $ 3.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518427
• 关键词: Albers-Schonberg disease; Automobile Driving; Back; Bone Diseases; Bone Marrow; Bone marrow failure; Bone structure; Cell Lineage; Communication; Complex; Coupling; Data; Disease; Family; Fracture; Infiltration; Lead; Ligands; Marrow; Modeling; Molecular; Mutation; NF-kappa B; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Parents; Pathway interactions; Production; Role; Signal Transduction; Stromal Cells; bone; bone cell; bone health; cost; improved; mouse model; novel; receptor; skeletal; training opportunity

Project Summary Proper bone structure relies on a complex interplay of molecular signals between bone resorbing osteoclasts (OCs) and bone forming osteoblasts (OBs). The integral role of OB lineage cells in OC formation, through production of receptor activator of NF-kB ligand (RANKL) and osteoprotegrin, is well described. However, for skeletal integrity to be maintained, bone formation must be matched to resorption - that is, OC must “talk back” to OB. While the mechanism of osteoclast:osteoblast coupling is poorly understood, it is clear that dysregulation of this interaction results in bone disease. At one end of the spectrum, resorption exceeds formation resulting in the common and costly osteoporosis and fractures. At the other end of the spectrum, bone formation continues despite dysfunctional OC with very low levels of resorption, resulting in OC-rich osteopetrosis (literally, “stone bone”). This rare family of diseases is characterized by abnormally dense, osteosclerotic bone. In its autosomal recessive form, osteopetrosis is potentially fatal due to stromal cell infiltration of the bone marrow and marrow failure. The parent R21 proposal seeks to obtain critical experimental support for the hypothesis that studying dysfunctional OC:OB coupling in osteopetrosis will reveal novel molecular mechanisms driving excess bone formation and replacement of the marrow niche with OC-misdirected OB. The proposed supplement project extends the analysis of osteopetrosis models to incorporate a mouse model of the very recently identified osteopetrosis due to mutations in SLC4A2.

项目摘要 正确的骨结构依赖于分离破骨细胞之间的分子信号的复杂相互作用 （OC）和骨形成成骨细胞（OBS）。 OB谱系细胞在OC形成中不可或缺的作用， 很好地描述了NF-KB配体（RANKL）和骨蛋白的受体激活剂的产生。但是，是 骨骼完整性要维护，骨形成必须与分辨率相匹配 - 也就是说，OC必须“回话” 对OB。骨细胞的机制：成骨细胞耦合的理解很少，但很明显失调 这种相互作用导致骨病。在频谱的一端，分辨率超出了形成，导致 常见且昂贵的骨质疏松和骨折。在光谱的另一端，骨形成继续。 尽管有功能失调的OC且分辨率非常低，但导致OC富集的骨质畸形（从字面上看，“石头 骨头”）。这种罕见的疾病系列的特征是绝对致密的骨硬膜骨。在其常染色体中 隐性形式，由于骨髓和骨髓的基质细胞浸润，骨质疏松症可能致命 失败。家长R21提案旨在为研究的假设获得关键的实验支持 功能失调的OC：骨质骨术中的OB耦合将揭示驱动的新型分子机制超过骨头 用OC-位指向OB的骨髓生态裂形成和替换。拟议的补充项目 扩展了骨质造成模型的分析，以结合最近确定的小鼠模型 由于SLC4A2突变而导致的骨质骨质膜。