A novel kindlin-2 regulatory pathway in bone remodeling

 描述(申请人提供)：骨重建是一个重要的过程，必须精确控制才能维持健康的生活，但控制这一过程的信号通路尚不完全清楚。这个探索性的项目利用了一种新的信号通路(即Kindlin-2通路)上令人兴奋的新发现，并试图确定它在骨重建中的作用。申请人的研究表明，成骨细胞(OBS)中Kindlin-2的缺失或Kindlin-2结合伙伴Migfilin的缺失会导致严重的骨量减少 提示Kindlin-2和Migfilin在骨重建中起着关键作用。Kindlin-2或Migfilin的缺失会损害OB的功能，并增加OBS中核因子kappa-B受体激活剂配体(RANKL)的表达，RANKL是主要的破骨因子。此外，有证据表明，Kindlin-2定位于细胞核，并调节OB基因的表达和分化。基于这些研究和其他研究，申请人假设Kindlin-2在OBS中的表达在控制骨重建中发挥关键作用，并通过与Migfilin和核转位的相互作用在这一过程中发挥作用。为了测试这一点，申请者提出了以下两个目标的研究。目的1确定Kindlin-2在活体OBS中的作用。申请者将详细分析Kindlin-2缺乏的影响 OB特异性Kindlin-2基因敲除小鼠体内OB行为和骨形成的研究。此外，申请者将确定Kindlin-2在OBS中调节RANKL表达、OCL分化和体内骨吸收中的作用。目的2是确定Kindlin-2在OBS中发挥作用的分子和细胞机制。申请者将确定Kindlin-2与Migfilin的相互作用和核转位在OB功能调控中的作用。此外，申请者还将评估Kindlin-2和Migfilin是否在骨重建的调节中存在遗传上的相互作用。尽管由于骨重建信号通路和机制的新颖性，该项目的风险相对较高，但它是非常有价值的，因为如果我们的假设得到拟议研究的验证，这将为控制骨重建的机制和治疗骨疾病的新策略开辟一条新的途径。

 DESCRIPTION (provided by applicant): Bone remodeling is an important process that must be precisely controlled in order to maintain a healthy life, but the signaling pathways that contro this process are incompletely understood. This exploratory project takes advantage of exciting new findings on a novel signaling pathway (i.e., the Kindlin-2 pathway) and seeks to define its role in bone remodeling. Studies by the applicants have shown that loss of Kindlin-2 in osteoblasts (OBs) or that of Migfilin, a Kindlin-2 binding partner, results in severe osteopenia in mice, suggesting a critical role of Kindlin-2 and Migfilin in bone remodeling. Depletion of either Kindlin-2 or Migfilin impairs OB functions and increased the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in OBs, a major osteoclastogenic factor. Furthermore, there is evidence suggesting that Kindlin-2 localizes to the nuclei and regulates OB gene expression and differentiation. Based on these and other studies, the applicants hypothesize that Kindlin-2 expression in OBs plays a critical role in controlling bone remodeling and it functions in this process through interaction with Migfilin and nuclear translocation. To test this the applicants propose studies with the following two aims. Aim 1 is to determine the role of Kindlin-2 in OBs in vivo. The applicants will analyze in detail the effects of Kindlin-2 deficiency on OB behavior and bone formation in vivo using OB-specific Kindlin-2 knockout mice. Furthermore, the applicants will determine the role of Kindlin-2 in regulation of RANKL expression in OBs, OCL differentiation and bone resorption in vivo. Aim 2 is to define the molecular and cellular mechanisms by which Kindlin-2 functions in OBs. The applicants will determine the roles of Kindlin-2 interaction with Migfilin and nuclear translocation in regulation f OB functions. Furthermore, the applicants will assess whether Kindlin-2 and Migfilin interact genetically in regulation of bone remodeling. Although this project is of relatively high risk due o the novelty of the proposed signaling pathway and mechanism in bone remodeling, it is highly rewarding, as if our hypothesis is validated by the proposed studies, this will open a new avenue of research on the mechanisms that control bone remodeling and new strategies for treatment of bone diseases.