Foxf1 Transcription Factor in Development of Pulmonary Capillaries

Foxf1转录因子在肺毛细血管发育中的作用

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV) is a lethal congenital disorder of neonates and infants caused by severe defects in development of pulmonary vasculature. Due to the severity of developmental defects and progressive respiratory insufficiency in ACD/MPV infants, mortality usually occurs within the first month of birth. There is no effective treatment for ACD/MPV patients, and new therapeutic approaches are greatly needed. Recently, dominantly inherited heterozygous mutations in the Forkhead Box F1 (FOXF1) gene were found in 40% of ACD/MPV cases. My laboratory previously demonstrated that FOXF1 transcription factor is a critical regulator of pulmonary vascular development. Global deletion of the mouse Foxf1 gene is embryonic lethal, whereas mice heterozygous for the Foxf1-null allele (Foxf1+/-) had reduced numbers of pulmonary capillaries, lung hypoplasia and increased perinatal mortality, all key features of human ACD/MPV. During the previous funding period, we generated mice with endothelial-specific deletion of Foxf1 and demonstrated that FOXF1 acts in cell autonomous manner to regulate angiogenesis and VEGF signaling in pulmonary endothelial cells. While 42 distinct FOXF1 mutations have been linked to ACD/MPV, molecular mechanisms by which these mutations perturb pulmonary morphogenesis and function remain unknown. We will focus on five distinct FOXF1 mutations that may have different pathogenesis in ACD/MPV. Our hypothesis is that FOXF1 mutations disrupt lung vascular development by inhibiting DNA binding (S52F and G91E mutations), interfering with function of wild type (WT) FOXF1 protein (Del872-879) or inactivating STAT3 signaling (Y284A and I285Q). In Aim 1, we will introduce the FOXF1 mutations into primary lung endothelial cells to determine molecular mechanisms by which these mutations disrupt cellular proliferation, migration and angiogenesis. We will also generate knock-in mice expressing one WT Foxf1 allele and one mutant Foxf1 allele, mimicking genetic abnormalities in ACD/MPV patients. We will use these mice to identify molecular mechanisms by which the FOXF1 mutations perturb pulmonary morphogenesis and function. We will also use a novel small molecule compound, which stabilizes WT FOXF1 protein, to stimulate development of pulmonary vasculature and improve survival in mouse ACD models. In Aim 2, using mass spectrometry we have already found that FOXF1 directly binds to the STAT3 protein, a key transcriptional regulator of endothelial cells. Thus, we will determine if FOXF1 functions as a co- activator of STAT3 to induce STAT3 signaling. We will also test whether disruption of FOXF1-STAT3 interactions by Y284A and I285Q FOXF1 mutations impairs pulmonary vascular development in vivo. Altogether, since reduced FOXF1 and STAT3 have been reported in several lung diseases, FOXF1-stabilizing compounds, which were recently identified in my laboratory, could have broad therapeutic applications for treatment of currently incurable ACD/MPV and other lung diseases associated with vascular insufficiency.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Vladimir Kalinichenko其他文献

Vladimir Kalinichenko的其他文献

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{{ truncateString('Vladimir Kalinichenko', 18)}}的其他基金

Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
  • 批准号:
    10891764
  • 财政年份:
    2023
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
  • 批准号:
    10055005
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
  • 批准号:
    10407550
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling
FOXM1在慢性肺重塑中调控的分子机制
  • 批准号:
    10170416
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
Transcriptional Regulation of Endothelial Cells after Acute Lung Injury
急性肺损伤后内皮细胞的转录调控
  • 批准号:
    9900064
  • 财政年份:
    2018
  • 资助金额:
    $ 39万
  • 项目类别:
Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury
新生儿肺损伤后内皮细胞的转录调控
  • 批准号:
    10661242
  • 财政年份:
    2018
  • 资助金额:
    $ 39万
  • 项目类别:
Transcriptional regulation of goblet cell metaplasia
杯状细胞化生的转录调控
  • 批准号:
    8744367
  • 财政年份:
    2014
  • 资助金额:
    $ 39万
  • 项目类别:
Transcriptional regulation of goblet cell metaplasia
杯状细胞化生的转录调控
  • 批准号:
    9279216
  • 财政年份:
    2014
  • 资助金额:
    $ 39万
  • 项目类别:
Fox Transcription Factors in Development of Pulmonary Capillaries
肺毛细血管发育中的 Fox 转录因子
  • 批准号:
    7414733
  • 财政年份:
    2006
  • 资助金额:
    $ 39万
  • 项目类别:
Foxf1 Transcription Factor in Development of Pulmonary Capillaries
Foxf1转录因子在肺毛细血管发育中的作用
  • 批准号:
    8242633
  • 财政年份:
    2006
  • 资助金额:
    $ 39万
  • 项目类别:

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