RANK Signaling in Osteoclast Differentiation and Function

破骨细胞分化和功能中的 RANK 信号转导

• 批准号: 7424166
• 负责人: XU FENG
• 金额: $ 2.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7424166
• 关键词: Adaptor Signaling Protein; B-Cell Development; Binding; Binding Sites; Bone Diseases; Commit; Cytoplasmic Tail; Data; Development; Family; Grant; In Vitro; Lead; MAPK14 gene; MAPK8 gene; Mammary gland; Mediating; Molecular; Mus; Mutation; NF-kappa B; Osteoclasts; Osteolysis; Pathway interactions; Play; Postmenopausal Osteoporosis; Proteins; Proto-Oncogene Proteins c-akt; Recruitment Activity; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Protein; System; TNF Receptor-Associated Factors; TNFSF11 gene; Therapeutic; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Yeasts; base; domain mapping; human TNF protein; in vivo; insight; lymph nodes; macrophage; member; novel; osteoclastogenesis; receptor; transcription factor; tumor; yeast two hybrid system

RANKL, also known as OPGL/ODF/TRANCE, is a member of the tumor necrosis factor (TNF) superfamily that plays an important role in osteoclast differentiation, function and survival. RANKL exerts these effects by binding to its receptor RANK, which is expressed on osteoclast precursors and mature osteoclasts. RANKL has been shown to activate six major signaling pathways: NF-kappa B, JNK, ERK, p38, NFATd and AKT. RANK belongs to the TNF receptor (TNFR) family and, hence, it transduces intracellular signals by recruiting various adaptor proteins including TNF receptor associated factors (TRAFs) through the specific motifs in the cytoplasmic domain. In the previous years of this grant we have characterized three TRAF-binding motifs that regulate osteoclast formation, function, and/or survival by activating one or more of the six known signaling pathways. Most importantly, however, we have also elucidated a 4-a.a. novel RANK cytoplasmic motif (IVVY535-538) that plays an essential role in osteoclastogenesis. This novel motif plays a crucial role in osteoclastogenesis by committing macrophages to the osteoclast lineage. Moreover, this RANK motif is NOT involved in the activation of the known RANK signaling pathways, indicating that it initiates a novel pathway(s). Based on these data, we hypothesize that, in addition to the known signaling pathways, RANK also activates an unidentified signaling pathway(s) critical for osteoclastogenesis through the novel motif. Thus, in the current application, we propose to identify and characterize the novel signaling pathways by investigating the following specific aims: 1) Investigate the functional relationship between the three TRAF-binding sites and the novel RANK motif; 2) Identify and characterize the downstream signaling protein that interacts with the novel RANK motif; 3) Investigate the role of the novel RANK motif in osteoclastogenesis in vivo by generating and characterizing knockin mice bearing an inactivating mutation in the novel RANK motif. The identification and characterization of the novel RANK signaling pathways will not only provide crucial insight into the molecular mechanism of osteoclastogenesis, but,more importantly, may lead to the development of more potent and specific therapeutics for various bone diseases including postmenopausal osteoporosis, boss loss in rheumatoid arthritis (RA) and tumor-induced osteolysis.

RANKL，也称为 OPGL/ODF/TRANCE，是肿瘤坏死因子 (TNF) 超家族的成员 在破骨细胞的分化、功能和存活中起着重要作用。 RANKL 发挥这些作用 通过与其受体 RANK 结合，该受体在破骨细胞前体和成熟破骨细胞上表达。 RANKL 已被证明可激活六种主要信号传导途径：NF-kappa B、JNK、ERK、p38、NFATd 和AKT。 RANK 属于 TNF 受体 (TNFR) 家族，因此它可以转导细胞内信号 通过招募各种接头蛋白，包括 TNF 受体相关因子 (TRAF) 细胞质结构域中的特定基序。在这笔赠款的前几年中，我们确定了三个特征 TRAF 结合基序通过激活一种或多种来调节破骨细胞的形成、功能和/或存活 六种已知的信号传导途径。然而，最重要的是，我们还阐明了 4-a.a。小说 RANK 细胞质基序 (IVVY535-538) 在破骨细胞生成中发挥重要作用。这个新颖的主题 通过使巨噬细胞进入破骨细胞谱系，在破骨细胞生成中发挥至关重要的作用。而且， 该 RANK 基序不参与已知 RANK 信号通路的激活，表明它 启动一条新途径。根据这些数据，我们假设，除了已知的信号传导之外 RANK 还通过以下方式激活对破骨细胞生成至关重要的未识别信号通路 小说的主题。因此，在当前的应用中，我们建议识别和表征新颖的信号传导 通过研究以下具体目标来研究路径： 1）研究 三个 TRAF 结合位点和新颖的 RANK 基序； 2) 识别并表征下游信令 与新的 RANK 基序相互作用的蛋白质； 3) 研究新颖的 RANK 主题在 通过生成和表征带有失活突变的敲入小鼠进行体内破骨细胞生成 在小说 RANK 主题中。新型 RANK 信号通路的鉴定和表征将 不仅提供了对破骨细胞生成的分子机制的重要见解，而且更重要的是， 可能会导致开发出更有效和更具体的治疗方法来治疗各种骨疾病，包括 绝经后骨质疏松症、类风湿性关节炎（RA）中的骨质流失和肿瘤引起的骨质溶解。