Lung developmental defects caused by type I collagen mutations in mouse models of osteogenesis imperfecta

成骨不全小鼠模型中 I 型胶原蛋白突变引起的肺发育缺陷

基本信息

  • 批准号:
    10735577
  • 负责人:
  • 金额:
    $ 39.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Patients with skeletal dysplasias, including osteogenesis imperfecta (OI), often suffer from congenital respiratory problems that have limited therapeutic opportunities, and increased perinatal and early childhood mortality. OI is caused by dominant mutations in COL1A1 and COL1A2 genes or by loss of function of genes involved in COL1 processing (e.g., CRTAP, encoding an essential protein for collagen post-translational modification and folding). The current concept is that the respiratory abnormalities in OI are secondary to the skeletal defects, such as thoracic wall deformities and deviations of the spine curvature (kyphoscoliosis), which do not allow proper expansion and inflation of the lungs leading to restrictive disease. We demonstrated that COL1 production is dysregulated in lung fibroblasts from a mouse model of OI lacking the Crtap gene (CrtapKO). These mice also exhibit defective lung alveolar formation, loss of alveolar epithelial cells, and several changes in genes expression, including decreased myofibroblast markers, as quantified by spatially resolved transcriptomics. In addition, CrtapKO mice and two others mouse models of OI with COL1 mutations (Col1a2G610C/+ and oim/oim) exhibit altered respiratory mechanics at 3 months of age. Based on this evidence and because COL1 is expressed in most tissues including the lung, our central hypothesis is that the respiratory defects in patients with OI and other skeletal dysplasias are due to intrinsic lung dysfunction that, in the future, could be treated and/or corrected independently from the skeletal fragility. The specific goals are 1) dissect the contribution of intrinsic lung defects versus extrinsic skeletal defects to impaired lung functions in OI; and 2) unravel cellular and molecular mechanisms triggered by COL1 defects leading to abnormal lung development and impaired respiratory function. To test our hypothesis, we assembled a team with complementary expertise that is uniquely positioned to accomplish our goals. The specific aims are: to determine the respiratory phenotype of a novel knock-in mouse model expressing a classical Col1a1 OI glycine substitution mutation in the lung but not in the skeleton (Col1a1Flox/+;Tbx4-Cre) and compare it to that of mice expressing this mutation globally (aim 1). To identify the cause of impaired alveolar morphogenesis and key pathways contributing to changes in alveolar mesenchymal-epithelial cell interactions in CrtapKO cell cultures and organoids (aim 2). To identify causes of impaired alveolar morphogenesis and abnormal patterning and function of lung cells in CrtapKO mice in vivo by analyzing the entire transcriptome in 5-7 µm lung sections with 100 µm or better lateral resolution during the critical stage of alveolar formation (aim 3). Together, aims 1-3 will provide mechanistic insights and establish the relationship between the collagen matrix and cellular dysfunction causing lung-intrinsic defects in OI leading to a better understanding of the role of the matrix in the last stage of lung development. Ultimately, this work will provide new insights into more common diseases of collagen dysregulation in the lung such as fibrosis and bronchopulmonary dysplasia.
患有骨骼发育不良(包括成骨不全(OI))的患者通常患有先天性呼吸道疾病。 这些问题限制了治疗机会,增加了围产期和幼儿死亡率。OI 是由COL 1A 1和COL 1A 2基因的显性突变引起的,或者是由参与 COL 1处理(例如,CRTAP,编码胶原蛋白翻译后修饰的必需蛋白, 折叠)。目前的概念是,OI的呼吸异常继发于骨骼缺陷, 例如胸壁畸形和脊柱弯曲的偏差(脊柱后凸), 肺的适当扩张和膨胀导致限制性疾病。我们证明了COL 1的产生 在来自缺乏Crtap基因(CrtapKO)的OI小鼠模型的肺成纤维细胞中失调。这些小鼠还 表现出有缺陷的肺泡形成,肺泡上皮细胞的损失,和几个基因的变化, 表达,包括减少的肌成纤维细胞标志物,如通过空间分辨转录组学定量的。在 此外,CrtapKO小鼠和另外两种具有COL 1突变的OI小鼠模型(Col 1a 2G 610 C/+和oim/oim) 在3个月大时表现出呼吸力学的改变。根据这一证据,由于COL 1是 在包括肺在内的大多数组织中表达,我们的中心假设是患者的呼吸缺陷 与OI和其他骨骼发育不良是由于内在的肺功能障碍,在未来, 和/或独立于骨骼脆弱性进行校正。具体目标是:1)剖析 内在肺缺陷与外在骨骼缺陷对OI肺功能受损的影响;以及2)阐明细胞 和COL 1缺陷引发的分子机制,导致肺发育异常和受损 呼吸功能为了验证我们的假设,我们组建了一个具有互补专业知识的团队, 有能力实现我们的目标具体目的是:确定一种新的呼吸系统表型, 在肺中表达经典Col 1a 1 OI甘氨酸取代突变但在肺中不表达的敲入小鼠模型 骨架(Col 1a 1Flox/+; Tbx 4-Cre),并将其与全面表达该突变的小鼠的骨架(aim 1)进行比较。到 确定肺泡形态发生受损的原因和导致肺泡 CrtapKO细胞培养物和类器官中的间充质-上皮细胞相互作用(目的2)。找出原因 在CrtapKO小鼠体内, 在5-7 µm肺切片中分析整个转录组,横向分辨率为100 µm或更高, 肺泡形成的关键阶段(目的3)。目标1-3将共同提供机械的见解,并建立 胶原基质和细胞功能障碍之间的关系,导致OI中的肺内在缺陷, 更好地了解基质在肺发育最后阶段的作用。最终,这项工作将 为肺中胶原蛋白失调的更常见疾病提供了新的见解,如纤维化和 支气管肺发育不良

项目成果

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ROY MORELLO其他文献

ROY MORELLO的其他文献

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{{ truncateString('ROY MORELLO', 18)}}的其他基金

Bone Histology and Imaging
骨组织学和成像
  • 批准号:
    10357775
  • 财政年份:
    2018
  • 资助金额:
    $ 39.41万
  • 项目类别:
Bone Histology and Imaging
骨组织学和成像
  • 批准号:
    10117263
  • 财政年份:
    2018
  • 资助金额:
    $ 39.41万
  • 项目类别:
Osteocytes in osteogenesis imperfecta (OI)
成骨不全症 (OI) 中的骨细胞
  • 批准号:
    10495748
  • 财政年份:
    2018
  • 资助金额:
    $ 39.41万
  • 项目类别:
Role of the Leprecan Genes in Skeletal Formation
妖精基因在骨骼形成中的作用
  • 批准号:
    8709813
  • 财政年份:
    2012
  • 资助金额:
    $ 39.41万
  • 项目类别:
Role of the Leprecan genes in skeletal formation
Leprecan 基因在骨骼形成中的作用
  • 批准号:
    8294284
  • 财政年份:
    2012
  • 资助金额:
    $ 39.41万
  • 项目类别:
Role of the Leprecan Genes in Skeletal Formation
妖精基因在骨骼形成中的作用
  • 批准号:
    8546299
  • 财政年份:
    2012
  • 资助金额:
    $ 39.41万
  • 项目类别:
Role of the Leprecan Genes in Skeletal Formation
妖精基因在骨骼形成中的作用
  • 批准号:
    8897266
  • 财政年份:
    2012
  • 资助金额:
    $ 39.41万
  • 项目类别:
Crtap function during skeletal homeostasis
骨骼稳态过程中的 Crtap 功能
  • 批准号:
    7053382
  • 财政年份:
    2005
  • 资助金额:
    $ 39.41万
  • 项目类别:
Crtap function during skeletal homeostasis
骨骼稳态过程中的 Crtap 功能
  • 批准号:
    6906326
  • 财政年份:
    2005
  • 资助金额:
    $ 39.41万
  • 项目类别:
Crtap function during skeletal homeostasis
骨骼稳态过程中的 Crtap 功能
  • 批准号:
    7278721
  • 财政年份:
    2005
  • 资助金额:
    $ 39.41万
  • 项目类别:
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