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): Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in preterm infants following mechanical ventilation and high levels of supplemental oxygen. While survival of premature newborns has increased due to recent improvements in perinatal care, BPD remains a serious and common complication of prematurity, affecting approximately 15,000 infants annually in USA. Infants with BPD are at higher risk of respiratory morbidity and mortality in early childhood. BPD has long-term respiratory and neurodevelopmental complications that reach beyond childhood and increase health care costs. Given the lack of major improvements in prevention and treatment of BPD, there is a major need for innovative molecular approaches to complement existing BPD therapies. Promising therapeutic approaches for BPD treatment include increasing postnatal angiogenesis and protection of alveolar endothelial cells from apoptosis after the injury caused by mechanical ventilation and high levels of oxygen. Based on our preliminary results, we believe that Forkhead Box F1 (Foxf1) transcription factor (also known as HFH-8 and Freac-1) plays a key role in both these processes and therefore, targeting the Foxf1 can be beneficial for both chemoprevention and treatment of children with BPD. Published studies from my laboratory have demonstrated that Foxf1 is expressed in pulmonary endothelial cells (EC) of embryonic and neonatal lungs. Mice heterozygous for the Foxf1 null allele exhibited lung hypoplasia, decreased number of alveolar capillaries, increased apoptosis of EC, and increased mortality in the early neonatal period. Genomic mutations in FoxF1 gene locus were recently found in 30% of human patients with Alveolar Capillary Dysplasia (ACD), a congenital lethal lung disease. Pulmonary Foxf1 mRNA and protein levels are reduced in newborn mice exposed to hyperoxia, a mouse model of BPD. Diminished Foxf1 levels are associated with loss of pulmonary vasculature in hyperoxia-treated newborn mice and human patients with BPD. Given the critical role of Foxf1 for pulmonary vascular development in mice and humans, it is important to determine the role of Foxf1 in the pathogenesis of BPD. We will use hyperoxia- mediated lung injury in newborn mice as a model of BPD to test the hypothesis that Foxf1 is required to maintain normal lung morphogenesis after hyperoxia injury by stimulating angiogenesis and increasing survival of endothelial cells. In Aim I, we will determine whether Foxf1 is required for formation of new pulmonary capillaries in a BPD model using two transgenic mouse lines with Foxf1 deficiency: Foxf1 mice and Tie2-Cre- fl/fl ER Foxf1 mice. In Aim II, we will determine whether Foxf1 directly regulates expression of anti-apoptotic genes and is required for survival of endothelial cells in a BPD model. Since the long-term goal of our studies is to find novel therapeutic agents preventing BPD in human patients, in Aim III we will determine whether increasing Foxf1 levels in neonatal lungs will accelerate vessel formation, increase EC survival and prevent BPD. Foxf1 levels in hyperoxia-treated newborn mice will be increased by either pharmacological approach (TAT-Foxf1 fusion protein) or genetic approach (Doxycycline-inducible over-expression of Foxf1 in endothelial cells). Completion of these studies will determine whether increasing Foxf1 levels is a promising therapeutic approach to prevent endothelial apoptosis and induce angiogenesis in BPD patients. PUBLIC HEALTH RELEVANCE: Foxf1 transcription factor is an important and clinically-relevant transcriptional regulator of pulmonary vascular development in mice and humans, but its role in Bronchopulmonary dysplasia (BPD) remains unknown. Using two novel mouse models with Foxf1 deficiency, we propose to determine whether Foxf1 is required to maintain postnatal lung morphogenesis by stimulating angiogenesis and increasing survival of endothelial cells (EC) after hyperoxia-mediated injury, a mouse model of BPD. We also propose to use cell-penetrating TAT-Foxf1 fusion protein, a novel therapeutic agent, to determine whether increasing Foxf1 in newborn mice will promote vascular repair after hyperoxia lung injury, decrease EC apoptosis and prevent BPD.
描述(申请人提供):支气管肺发育不良(BPD)是一种慢性肺部疾病,发生在早产儿机械通气和高水平的补充氧气。虽然由于最近围产期护理的改善,早产儿的存活率有所增加,但BPD仍然是早产儿的严重和常见的并发症,在美国每年约有15,000名婴儿受到影响。患有BPD的婴儿在儿童早期患呼吸道疾病和死亡的风险更高。BPD有长期的呼吸道和神经发育并发症,影响范围超出童年,并增加医疗费用。鉴于在预防和治疗BPD方面缺乏重大改进,迫切需要创新的分子方法来补充现有的BPD疗法。治疗BPD的有前景的治疗方法包括增加出生后血管生成和保护机械通气和高氧损伤后的肺泡内皮细胞免于凋亡。根据我们的初步结果,我们认为Forkhead Box F1(Foxf1)转录因子(也称为HfH-8和Freac-1)在这两个过程中发挥关键作用,因此,靶向Foxf1对BPD儿童的化学预防和治疗都是有益的。我的实验室发表的研究表明,Foxf1在胚胎和新生儿肺的肺内皮细胞(EC)中表达。携带Foxf1零基因杂合子的小鼠在新生早期表现出肺发育不良、肺泡毛细血管数量减少、内皮细胞凋亡增加和死亡率增加。最近在30%的人类肺泡毛细血管发育不良(ACD)患者中发现了FoxF1基因突变,ACD是一种先天性致死性肺部疾病。暴露在高氧环境中的新生小鼠的肺Foxf1基因和蛋白水平降低,这是BPD的一种小鼠模型。在高氧处理的新生小鼠和患有BPD的人类患者中,Foxf1水平降低与肺血管丧失有关。鉴于Foxf1在小鼠和人类肺血管发育中的关键作用,确定Foxf1在BPD发病机制中的作用是重要的。我们将使用高氧介导的新生小鼠肺损伤作为BPD的模型,以验证Foxf1在高氧损伤后需要通过刺激血管生成和增加内皮细胞存活来维持正常的肺形态发生的假说。在目标I中,我们将使用两个带有Foxf1缺陷的转基因小鼠系:Foxf1小鼠和Tie2-Cre-fl/fl ER Foxf1小鼠,确定在BPD模型中是否需要Foxf1来形成新的肺毛细血管。在AIM II中,我们将确定Foxf1是否直接调节抗凋亡基因的表达,并且是BPD模型中内皮细胞生存所必需的。由于我们研究的长期目标是寻找新的治疗药物来预防人类患者的BPD,在目标III中,我们将确定增加新生儿肺中Foxf1的水平是否会加速血管形成,增加EC存活率和预防BPD。通过药理学方法(TAT-Foxf1融合蛋白)或遗传方法(多西环素诱导内皮细胞中Foxf1的过度表达),高氧处理的新生小鼠的Foxf1水平将会增加。这些研究的完成将确定增加Foxf1水平是否是预防BPD患者内皮细胞凋亡和诱导血管生成的有前景的治疗方法。 公共卫生相关性:Foxf1转录因子是小鼠和人类肺血管发育的重要和临床相关的转录调节因子,但它在支气管肺发育不良(BPD)中的作用尚不清楚。使用两种新的Foxf1缺乏的小鼠模型,我们建议确定在BPD的小鼠模型--高氧介导的损伤后,是否需要Foxf1通过刺激血管生成和增加内皮细胞(EC)的存活来维持出生后肺的形态发生。我们还建议使用一种新的治疗剂TAT-Foxf1融合蛋白来确定增加新生小鼠Foxf1是否会促进高氧肺损伤后的血管修复,减少EC凋亡和预防BPD。

项目成果

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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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    $ 38.25万
  • 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:
    9065597
  • 财政年份:
    2006
  • 资助金额:
    $ 38.25万
  • 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:
    $ 38.25万
  • 项目类别:

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