Project 1: The role of WNT1 signaling in osteogenesis imperfecta

项目1项目总结 成骨不全(OI)是最常见的骨骼发育不良之一。大多数病例都是由 由I型胶原的定性或定量缺陷引起。我们之前已经鉴定了致病的 CRTAP和P3H1基因突变导致隐性遗传性OI的机制 脯氨基-3-羟基化复合体。我们还发现了信号分子PEDF、IFITM5和 WNT1引起隐性OI。重要的是，我们的WNT1发现确定了第一个特定的WNT配体 人类骨骼发育不良。令人惊讶的是，WNT1最为人所知的是它在神经脊和小脑中的功能 虽然它在骨骼中的基本功能令人惊讶。因此，有许多未回答的问题 关于WNT1相关OI的问题：1)WNT1在骨骼中的组织特异性要求是什么？2) 哪些信号通路介导了WNT1在骨骼中的功能？3)靶向WNT信号的治疗方法能否显示 不同OI类型的不同疗效？4)其他哪些Wnt信号通路基因与OI和/或Low有关 骨量？项目1的目标是了解WNT1在骨骼发育和骨发育中的功能。 动态平衡；确定WNT1突变导致OI的致病机制；检测 抗硬化素抗体治疗WNT1相关OI与其他类型OI的潜力；并确定新的 导致OI的WNT和胶原修饰途径中的基因。我们的初步数据显示，WNT1 突变小鼠(摇摆)表现出自发性骨折和骨量减少。此外，过度表达 WNT1在体外促进成骨细胞分化并激活mTORC1信号通路。我们假设WNT1 在骨细胞中的表达通过调节成骨细胞中的mTORC1信号来促进骨内环境的稳定。我们 将通过实现以下具体目标来检验这一假设：目标1.什么是组织和细胞- WNT1对骨骼发育和动态平衡的特殊贡献？目标2.下游是什么 介导WNT1在骨骼发育和动态平衡中作用的信号通路？目标3.什么是 WNT靶向治疗对不同形式的OI的影响？目标4.有没有罕见的OI形式可以识别 骨骼中胶原蛋白加工和/或Wnt信号的新的和必要的成分？

Project 1 Project Summary Osteogenesis imperfecta (OI) is one of the most common skeletal dysplasias. Most cases are caused by either qualitative or quantitative defects in type I collagen. We previously identified the pathogenic mechanism of recessively inherited OI caused by CRTAP and P3H1 mutations, components of a collagen prolyl 3-hydroxylation complex. We also identified mutations in the signaling molecules PEDF, IFITM5, and WNT1 causing recessive OI. Importantly, our WNT1 finding identified the first specific WNT ligand involved in a human skeletal dysplasia. Surprisingly, WNT1 is best known for its functions in neural crest and cerebellar development, while its essential function in bone was a surprise. Hence, there are many unanswered questions regarding WNT1-related OI: 1) What are the tissue-specific requirements of WNT1 in bone? 2) Which signaling pathways mediate WNT1 function in bone? 3) Can therapeutics that target Wnt signaling show differential efficacy in distinct OI types? 4) What other Wnt-signaling pathway genes contribute to OI and/or low bone mass? The goals of Project 1 are to understand the functions of WNT1 in bone development and homeostasis; to identify the pathogenic mechanisms by which mutations in WNT1 lead to OI; to test the potential of anti-sclerostin antibody treatment for WNT1-related vs. other types of OI; and to identify novel genes in the WNT and collagen modification pathway leading to OI. Our preliminary data show that Wnt1 mutant mice (swaying) exhibit spontaneous fractures and reduced bone mass. Moreover, overexpression of Wnt1 increases osteoblast differentiation and activates mTORC1 signaling in vitro. We hypothesize that Wnt1 expressed in osteocytes contributes to bone homeostasis by regulating mTORC1 signaling in osteoblasts. We will test this hypothesis by accomplishing the following specific aims: Aim 1. What are the tissue and cell- specific contributions of Wnt1 to skeletal development and homeostasis? Aim 2. What are the downstream signaling pathways that mediate Wnt1 functions in skeletal development and homeostasis? Aim 3. What are the effects of Wnt-targeted therapies in different forms of OI? Aim 4. Are there rare forms of OI that identify new and essential components of collagen processing and/or Wnt signaling in bone?