Etiology and pathogenesis of lethal lung developmental disorders in neonates

新生儿致命性肺发育障碍的病因和发病机制

基本信息

  • 批准号:
    10660107
  • 负责人:
  • 金额:
    $ 79.34万
  • 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:
    2023-08-15 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary Lethal lung developmental disorders (LLDDs) are rarely diagnosed but devastating pulmonary hypoplasias (PHs), presenting with progressive neonatal hypoxia and severe pulmonary arterial hypertension (PAH). Based on histopathological appearance, LLDDs have been traditionally classified as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary PHs. We found that heterozygous single nucleotide variants (SNVs) in the mesenchymal transcription factor (TF) FOXF1 gene or copy-number variant (CNV) deletions involving FOXF1 or its lung-specific enhancer located ~ 300 kb upstream are responsible for ACDMPV in 80-90% of patients. We reported that this enhancer also up-regulates in cis lncRNA FENDRR mapping nearby FOXF1. Interestingly, unlike SNVs, CNV deletions arise almost exclusively on the maternal chromosome 16. Recently, we and others demonstrated the causative role for variants in another mesenchymal TF, TBX4, and a paracrine signaling molecule FGF10 in greater than 60% of infants with AcDys, CAD, and other primary PHs, indicating the significance also of TBX4-FGF10 signaling in pathogenesis of LLDDs. Importantly, FOXF1 and TBX4 variants have been associated also with more common idiopathic or familial childhood PAH. Interestingly, we found a statistically significant enrichment of non-coding SNVs in the FOXF1 and TBX4 enhancers in patients with variable presentation of LLDD. Moreover, our ChIP-seq and RNA-seq studies have implied interactions between the SHH-FOXF1 and TBX4-FGF10 signaling pathways, involving little-known lung-specific endothelial transmembrane protein TMEM100. We hypothesize that (i) non-coding SNVs within the regulatory regions of lung developmental genes can dramatically modify (alleviate or exacerbate) LLDD and PAH phenotypes, (ii) an interplay between the coding and non-coding variants can explain the complex compound inheritance observed in families with LLDDs and PAH, and (iii) interaction of SHH-FOXF1 and TBX4-FGF10 signaling pathways, involving TMEM100, is required for proper human lung development. Using human lung specimens and cell lines and mouse models, we will identify and analyze non-coding regulatory elements of FOXF1 in patients with ACDMPV and/or PAH (Aim 1) and those of TBX4 and FGF10 in patients with AcDys, CAD, other PHs, and/or PAH (Aim 2). In Aim 3, we will decipher the crosstalk between SHH-FOXF1 and TBX4-FGF10 epithelial- mesenchymal signaling, involving TMEM100, to untangle the complex compound inheritance in families with LLDDs and PAH. Our studies will elucidate the genetics of lung development in humans and how its perturbations translate to phenotypic variability of LLDDs and PAH. We will identify new genetic variants, allowing for more precise diagnosis and prognosis of these disorders, facilitating more informative genetic counseling, and providing targets for development of potential in utero treatments for LLDDs and PAH. Our data will also help to better understand incomplete penetrance and variable expressivity phenomena in human genetics in general.
项目总结

项目成果

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PAWEL STANKIEWICZ其他文献

PAWEL STANKIEWICZ的其他文献

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{{ truncateString('PAWEL STANKIEWICZ', 18)}}的其他基金

Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
  • 批准号:
    9922356
  • 财政年份:
    2017
  • 资助金额:
    $ 79.34万
  • 项目类别:
Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
  • 批准号:
    9287627
  • 财政年份:
    2017
  • 资助金额:
    $ 79.34万
  • 项目类别:
Unrecognized scale and clinical relevance of somatic mosaicism
体细胞嵌合体的规模和临床相关性未被认识
  • 批准号:
    10011833
  • 财政年份:
    2017
  • 资助金额:
    $ 79.34万
  • 项目类别:
Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
  • 批准号:
    9767850
  • 财政年份:
    2017
  • 资助金额:
    $ 79.34万
  • 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
  • 批准号:
    8460859
  • 财政年份:
    2010
  • 资助金额:
    $ 79.34万
  • 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
  • 批准号:
    8259439
  • 财政年份:
    2010
  • 资助金额:
    $ 79.34万
  • 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
  • 批准号:
    7862026
  • 财政年份:
    2010
  • 资助金额:
    $ 79.34万
  • 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
  • 批准号:
    8063912
  • 财政年份:
    2010
  • 资助金额:
    $ 79.34万
  • 项目类别:

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  • 批准号:
    10726763
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肝肺综合征低氧血症的新肺泡机制
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