A novel kindlin-2 regulatory pathway in bone remodeling

 描述（由申请人提供）：骨重建是一个重要的过程，必须精确控制，以维持健康的生活，但控制这一过程的信号通路尚未完全了解。这个探索性的项目利用了令人兴奋的新发现的一种新的信号通路（即，Kindlin-2途径），并试图确定其在骨重建中的作用。申请人的研究已经表明，成骨细胞（OB）中Kindlin-2的丢失或Kindlin-2结合配偶体Migfilin的丢失导致成骨细胞（OB）中严重的骨质减少。 小鼠，表明Kindlin-2和Migfilin在骨重建中的关键作用。Kindlin-2或Migfilin的缺失损害OB功能，并增加OB中核因子κ-B配体受体激活因子（RANKL）（一种主要的破骨细胞生成因子）的表达。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。基于这些和其他研究，申请人假设OB中的Kindlin-2表达在控制骨重建中起关键作用，并且其通过与Migfilin和核转位的相互作用在该过程中起作用。为了验证这一点，申请人提出了具有以下两个目的的研究。目的1：探讨Kindlin-2在OBs中的作用。申请人将详细分析Kindlin-2缺陷的影响 使用OB特异性Kindlin-2敲除小鼠对OB行为和体内骨形成的影响。此外，申请人将确定Kindlin-2在体内调节OB中RANKL表达、OCL分化和骨吸收中的作用。目的2是确定Kindlin-2在OB中发挥作用的分子和细胞机制。申请人将确定Kindlin-2与Migfilin的相互作用和核转位在调节OB功能中的作用。此外，申请人将评估Kindlin-2和Migfilin是否在调节骨重建中发生遗传相互作用。虽然由于所提出的骨重建信号通路和机制的新奇，该项目具有相对较高的风险，但它是非常有价值的，因为如果我们的假设被所提出的研究证实，这将为控制骨重建的机制的研究开辟新的途径，并为骨疾病的治疗开辟新的策略。

 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.