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: 7146856
• 负责人: XU FENG
• 金额: $ 28.81万
• 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/7146856
• 关键词: binding proteins; biological signal transduction; cell differentiation; colony stimulating factor; cytokine receptors; gene targeting; genetically modified animals; laboratory mouse; macrophage; nuclear factor kappa beta; osteoclasts; physiologic bone resorption; protein structure function; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): 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, NFATc1 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.

描述（由申请人提供）：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、功能和存活中发挥重要作用。 RANKL 通过与其受体 RANK 结合来发挥这些作用，RANK 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通路：NF-kappa B、JNK、ERK、p38、NFATc1 和 AKT。 RANK 属于 TNF 受体 (TNFR) 家族，因此，它通过细胞质结构域中的特定基序招募各种接头蛋白（包括 TNF 受体相关因子 (TRAF)）来转导细胞内信号。在这笔资助的前几年，我们已经表征了三个 TRAF 结合基序，它们通过激活六种已知信号通路中的一个或多个来调节破骨细胞的形成、功能和/或存活。然而，最重要的是，我们还阐明了 4-a.a。新型 RANK 细胞质基序 (IVVY535-538) 在破骨细胞生成中发挥重要作用。这种新颖的基序通过将巨噬细胞定向到破骨细胞谱系中，在破骨细胞生成中发挥着至关重要的作用。此外，该 RANK 基序不参与已知 RANK 信号通路的激活，表明它启动了一条新的通路。基于这些数据，我们假设，除了已知的信号通路外，RANK 还通过新的基序激活对破骨细胞生成至关重要的未知信号通路。因此，在当前的应用中，我们建议通过研究以下具体目标来识别和表征新的信号通路：1）研究三个TRAF结合位点与新的RANK基序之间的功能关系； 2) 鉴定并表征与新型 RANK 基序相互作用的下游信号蛋白； 3) 通过生成和表征新型 RANK 基序中带有失活突变的敲入小鼠，研究新型 RANK 基序在体内破骨细胞生成中的作用。新型 RANK 信号通路的鉴定和表征不仅将为破骨细胞生成的分子机制提供重要的见解，更重要的是，可能会导致针对各种骨疾病（包括绝经后骨质疏松症、骨质疏松症等）开发出更有效和更特异性的治疗方法。类风湿性关节炎（RA）和肿瘤引起的骨溶解。