A novel kindlin-2 regulatory pathway in bone remodeling

骨重塑中的新型kindlin-2调控途径

• 批准号: 8891568
• 负责人: CHUANYUE WU
• 金额: $ 21.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891568
• 关键词: Ablation; Adhesions; Behavior; Binding; Binding Sites; Bone Diseases; Bone Marrow; Bone Resorption; Bone remodeling; Cell Nucleus; Defect; Development; Extracellular Matrix; Figs - dietary; Focal Adhesions; Gene Expression; Human; Integrins; Knockout Mice; Life; Light; Location; Mediating; Metabolic Bone Diseases; Molecular; Mus; Mutate; New Agents; Nuclear; Nuclear Translocation; Osteoblasts; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Pathway interactions; Phenotype; Play; Process; Proteins; Regulation; Regulatory Pathway; Research; Rewards; Role; Signal Pathway; Signal Transduction; Stromal Cells; TRANCE protein; Testing; Therapeutic; Tissues; base; bone; design; high risk; human disease; in vivo; migration; mutant; novel; osteoblast differentiation; prevent; public health relevance; research study; skeletal; treatment strategy

 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.

 描述（由申请人提供）：骨重塑是一个重要的过程，必须精确控制才能维持健康的生活，但控制该过程的信号传导途径尚未完全了解，该探索性项目利用了一项新颖的令人兴奋的新发现。申请人的研究表明成骨细胞（OB）或成骨细胞中Kindlin-2的丢失。 Migfilin 是 Kindlin-2 的结合伴侣，可导致严重的骨质减少 小鼠，表明 Kindlin-2 和 Migfilin 在骨重塑中发挥关键作用 Kindlin-2 或 Migfilin 的缺失会损害 OB 功能并增加 OB 中核因子 kappa-B 配体受体激活剂 (RANKL) 的表达，这是一种主要的破骨细胞。此外，有证据表明 Kindlin-2 定位于细胞核并调节 OB 基因表达和分化。基于这些和其他研究，申请人寻求这一点。 Kindlin-2 在 OB 中的表达在控制骨重塑中发挥着关键作用，它通过与 Migfilin 和核易位的相互作用来发挥作用。为了测试这一点，申请人的提案研究的目的 1 是确定 Kindlin 的作用。 -2 在体内 OB 中，申请人将详细分析 Kindlin-2 缺陷的影响。 此外，申请人将确定 Kindlin-2 在 OB 中 RANKL 表达、OCL 分化和体内骨吸收的调节中的作用。定义 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 相互作用以及核易位在调节 OB 功能中的作用。 Kindlin-2 和 Migfilin 在骨重塑调节中存在遗传相互作用，尽管由于所提出的骨重塑信号通路和机制的新颖性，该项目具有相对较高的风险，但它是非常有价值的，就好像我们的假设得到了所提出的验证一样。研究，这将为控制骨重塑的机制和治疗骨疾病的新策略开辟一条新的研究途径。