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Project 1: The role of WNT1 signaling in osteogenesis imperfecta

Project 1: The role of WNT1 signaling in osteogenesis imperfecta
项目1:WNT1信号在成骨不全症中的作用
批准号:
9184865
负责人:
Brendan Lee
金额:
$42.96万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至

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中文摘要
翻译
项目1项目概要 成骨不全是最常见的骨骼发育不良之一。大多数病例是由 通过I型胶原质的定性或定量缺陷。我们之前发现了 CRTAP和P3 H1突变引起的复发性遗传性OI的机制,胶原蛋白的成分 脯氨酰3-羟基化复合物。我们还鉴定了信号分子PEDF、IFITM 5和 WNT 1引起隐性OI。重要的是,我们的WNT 1发现确定了第一个参与免疫应答的特异性WNT配体。 人类骨骼发育不良令人惊讶的是,WNT 1最为人所知的是其在神经嵴和小脑中的功能。 然而,它在骨骼中的基本功能却令人惊讶。因此,有许多未回答的问题 关于WNT 1相关OI的问题:1)WNT 1在骨中的组织特异性要求是什么?(二) 哪些信号通路介导WNT 1在骨中的功能?3)靶向Wnt信号传导的疗法是否能显示 不同类型OI的疗效差异?4)还有哪些Wnt信号通路基因导致OI和/或低血糖 骨量?项目1的目标是了解WNT 1在骨发育中的功能, 体内平衡;确定WNT 1突变导致OI的致病机制;检测 抗sclerostin抗体治疗WNT 1相关与其他类型OI的潜力;并鉴定新的 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,Wnt 1 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 Wnt 1在体外增加成骨细胞分化并激活mTORC 1信号传导。我们假设Wnt 1 在骨细胞中表达的mTORC 1通过调节成骨细胞中的mTORC 1信号传导而有助于骨稳态。我们 我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- Wnt 1对骨骼发育和稳态的具体贡献?目标二。下游有哪些 在骨骼发育和稳态中介导Wnt 1功能的信号通路?目标3:是什么 Wnt靶向治疗在不同形式的OI中的作用?目标4。是否有罕见的OI形式, 骨中胶原蛋白加工和/或Wnt信号传导的新的和必要的成分?
英文摘要
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?
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Targeting TGFb In Osteogenesis Imperfecta
  • 批准号:
    10736736
  • 项目类别:
  • 资助金额:
    $62.59万
  • 财政年份:
    2023
  • 负责人:
    Brendan Lee
  • 依托单位:
Regulation of Skeletal progenitor cells in Osteogenesis Imperfecta
  • 批准号:
    10528208
  • 项目类别:
  • 资助金额:
    $66.24万
  • 财政年份:
    2022
  • 负责人:
    Brendan Lee
  • 依托单位:
Regulation of Skeletal progenitor cells in Osteogenesis Imperfecta
  • 批准号:
    10665057
  • 项目类别:
  • 资助金额:
    $66.24万
  • 财政年份:
    2022
  • 负责人:
    Brendan Lee
  • 依托单位:
ALL OF US EVENINGS WITH GENETICS RESEARCH EDUCATION PROGRAM
  • 批准号:
    10307410
  • 项目类别:
  • 资助金额:
    $108.91万
  • 财政年份:
    2021
  • 负责人:
    Brendan Lee
  • 依托单位:
海外基金