Elucidating the Relationship Between Notch and WNT Signaling in Bone Formation

阐明 Notch 和 WNT 信号在骨形成中的关系

• 批准号: 8264958
• 负责人: Courtney Michael Karner
• 金额: $ 5.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264958
• 关键词: Affect; Alleles; Bone Development; Bone Marrow; Bone Matrix; Bone remodeling; Cells; Development; Disease; Doxycycline; Embryonic Development; Excision; Genetic; Goals; Homeostasis; Individual; Lead; Light; Mesenchymal; Mus; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Phenotype; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Staging; Testing; WNT Signaling Pathway; bone; bone mass; cell type; notch protein; novel; novel therapeutic intervention; osteoblast differentiation; progenitor; public health relevance

DESCRIPTION (provided by applicant): During embryogenesis, the Notch/RBPjk and Wnt/2-catenin signaling pathways regulate diverse cell fate decisions. Osteoblasts are the primary cell type responsible for producing bone matrix and are necessary not only for bone development but also bone remodeling and homeostasis. Deficiency in osteoblast differentiation results in osteoporosis, a disease characterized by significant decreases in bone mass. During osteoblast development, Notch/RBPjk signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Conversely, Wnt/2-catenin signaling promotes osteoblast differentiation. The disparate effects of these two pathways are clear, with Notch inhibiting differentiation while Wnt promoting it. However, the exact stage at which Notch inhibits osteoblast development has not been defined, although our preliminary studies indicate that Notch likely impedes further progression of Runx2- positive cells. Moreover, the genetic relationship between Wnt and Notch pathways during osteoblast differentiation is not known. As such, the goal of this proposal is to test the hypothesis that Notch suppresses further differentiation of Runx2-positive cells and that Notch functions at least in part by inhibiting Wnt/ -catenin signaling. To test this hypothesis I have developed two specific aims. Aim 1. Determine the role of Notch/RBPjk signaling in Runx2-positive cells during osteoblast differentiation I will use a novel mouse line to delete RBPjk in Runx2-positive cells in a doxycycline-inducible manner and to assess the potential bone phenotype. This study will provide genetic evidence about the stage-specific regulation of osteoblast differentiation by Notch/RBPjk signaling. Aim 2. Evaluate the genetic relationship between RBPjk and -catenin during osteoblast development I will examine the effect of -catenin removal (single or both alleles) on the high-bone-mass phenotype caused by RBPjk deletion in mesenchymal progenitors. This study will test the hypothesis that Notch/RBPjk functions genetically upstream of Wnt/ -catenin signaling during osteoblast differentiation. Overall, these studies will enhance the current understanding about Notch inhibition of osteoblast differentiation, and shed light on the functional relationship between two opposing signals, Notch and Wnt, during osteoblast development. PUBLIC HEALTH RELEVANCE: Osteoporosis is a major public health problem affecting approximately 75 million individuals worldwide. Findings from these studies may lead to novel therapeutic approaches to the treatment of this disease.

描述（由申请人提供）：在胚胎发生期间，Notch/RBPJK和Wnt/2-catenin信号通路调节各种细胞命运的决策。成骨细胞是负责产生骨基质的主要细胞类型，不仅对于骨发育，而且对于骨重塑和稳态都是必不可少的。成骨细胞分化的缺乏会导致骨质疏松症，这种疾病的特征是骨骼质量显着降低。在成骨细胞发育过程中，Notch/RBPJK信号传导通过抑制成骨细胞分化来保持骨髓间充质祖细胞。相反，Wnt/2-catenin信号传导促进成骨细胞分化。这两种途径的不同影响很明显，在促进它的同时，缺口抑制了分化。然而，尽管我们的初步研究表明Notch可能阻碍Runx2-阳性细胞的进一步发展，但尚未定义Notch抑制成骨细胞发育的确切阶段。此外，在成骨细胞分化过程中Wnt和Notch途径之间的遗传关系尚不清楚。因此，该提案的目的是测试Notch抑制Runx2阳性细胞进一步分化的假设，并且Notch至少部分通过抑制Wnt/ -Catenin信号传导而发挥作用。为了检验这一假设，我已经开发了两个具体目标。 AIM 1。确定成骨细胞分化过程中Notch/RBPJK信号传导在Runx2阳性细胞中的作用，我将使用新型的小鼠系在Runx2阳性细胞中以强力线诱导的方式删除RBPJK并评估潜在的骨骼表型。这项研究将提供有关Notch/RBPJK信号传导对成骨细胞分化的特异性调节的遗传证据。 AIM 2。在成骨细胞发育过程中评估RBPJK和-CATENIN之间的遗传关系I将检查 - 胞质递减中RBPJK缺失引起的高骨质量表型的去除（单位或两个等位基因）的影响。这项研究将检验以下假设：在成骨细胞分化过程中Wnt/ -Catenin信号在遗传上的Notch/ RBPJK功能。 总体而言，这些研究将增强对成骨细胞分化的缺口抑制的当前理解，并阐明在成骨细胞开发过程中两个相对信号Notch和Wnt之间的功能关系。 公共卫生相关性：骨质疏松症是影响全球约7500万个人的主要公共卫生问题。这些研究的发现可能导致治疗这种疾病的新型治疗方法。