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）：在胚胎发生过程中，Notch/RBPjk和Wnt/2-catenin信号通路调节不同的细胞命运决定。成骨细胞是产生骨基质的主要细胞类型，不仅是骨发育所必需的，而且是骨重塑和体内平衡所必需的。成骨细胞分化不足导致骨质疏松症，这是一种以骨量显著减少为特征的疾病。在成骨细胞发育过程中，Notch/RBPjk信号通过抑制成骨细胞分化来维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。这两种通路的不同作用是明确的，Notch抑制分化而Wnt促进分化。然而，Notch抑制成骨细胞发育的确切阶段尚未确定，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。此外，在成骨细胞分化过程中，Wnt和Notch通路之间的遗传关系尚不清楚。因此，本提案的目的是验证Notch抑制runx2阳性细胞进一步分化的假设，以及Notch至少部分通过抑制Wnt/ -catenin信号传导发挥作用。为了验证这一假设，我制定了两个具体目标。目的1。确定Notch/RBPjk信号在runx2阳性细胞成骨分化过程中的作用我将使用一种新的小鼠系，以强西环素诱导的方式删除runx2阳性细胞中的RBPjk，并评估潜在的骨表型。本研究将为Notch/RBPjk信号对成骨细胞分化的阶段性调控提供遗传学证据。目标2。在成骨细胞发育过程中评估RBPjk和-catenin之间的遗传关系我将研究-catenin去除（单个或两个等位基因）对间充质祖细胞中RBPjk缺失引起的高骨量表型的影响。本研究将验证Notch/RBPjk在成骨细胞分化过程中发挥Wnt/ -catenin信号上游遗传功能的假设。总之，这些研究将加深目前对Notch抑制成骨细胞分化的理解，并揭示成骨细胞发育过程中两个对立信号Notch和Wnt之间的功能关系。