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

批准号：
8242633
负责人：
Vladimir Kalinichenko
金额：
$ 38.25万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242633
关键词：
Affect Alleles Alveolar Apoptosis Apoptotic Blood Circulation Blood Vessels Blood capillaries Boxing Breeding Bronchopulmonary Dysplasia Cell Survival Cells Chemoprevention Child Childhood Chimeric Proteins Chronic lung disease Complement Complication Development Doxycycline Dysplasia Embryo Embryonic Development Endothelial Cells Exhibits Fetal Lung Gene Expression Genes Genetic Genomics Goals Health Care Costs Human Hyperoxia In Vitro Infant Injury Integrins Laboratories Lung Lung diseases Mechanical ventilation Mediating Messenger RNA Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Mutation Neonatal Newborn Infant Oxygen Pathogenesis Patients Perinatal Care Play Pneumonia Premature Infant Prevention Process Proteins Publishing Pulmonary vessels Reporter Role Severities Signal Pathway Structure of parenchyma of lung Testing Therapeutic Therapeutic Agents Transgenic Mice Tube Vascular Endothelial Growth Factor Receptor angiogenesis base capillary cell motility clinically relevant early childhood high risk in vivo innovation lung injury lung repair matrigel mortality mouse model mutant novel novel therapeutics postnatal premature prevent public health relevance repaired respiratory response transcription factor

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（由申请人提供）：支气管肺发育不良（BPD）是一种慢性肺部疾病，在机械通气和高水平的补充氧气后发生在早产儿中。尽管由于最近的围产期护理改善，早产新生儿的生存率增加了，但BPD仍然是早产的严重且普遍的并发症，每年在美国影响约15,000名婴儿。 BPD婴儿在幼儿期的呼吸道发病和死亡率的风险更高。 BPD具有长期的呼吸和神经发育并发症，超出了儿童期并增加医疗保健成本。鉴于BPD的预防和治疗缺乏重大改善，因此需要创新的分子方法来补充现有的BPD疗法。 BPD治疗的有前途的治疗方法包括增加产后血管生成和保护肺泡内皮细胞免受机械通气和高氧气损伤后的细胞凋亡的保护。根据我们的初步结果，我们认为叉子盒F1（FOXF1）转录因子（也称为HFH-8和FREAC-1）在这两个过程中都起着关键作用，因此，靶向FOXF1可能对BPD儿童的化学预防和治疗都有益。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。 FOXF1 NULL等位基因的杂合小鼠表现出肺部发育不全，肺泡毛细血管数量减少，EC的凋亡增加，并在新生儿初期死亡率增加。最近在30％的患有先天性致死性肺部疾病的人类肺泡毛细血管发育不全（ACD）患者中发现了30％的FOXF1基因基因座的基因组突变。暴露于Hyperoxia（BPD小鼠模型）的新生小鼠中，肺FOXF1 mRNA和蛋白质水平降低。 FOXF1水平降低与高氧治疗的新生小鼠和BPD患者的肺血管丧失有关。鉴于FOXF1在小鼠和人类中的肺血管发育的关键作用，确定FOXF1在BPD发病机理中的作用很重要。我们将使用新生小鼠中的高氧介导的肺损伤作为BPD模型，以检验以下假设：通过刺激血管生成和增加内皮细胞存活的高氧损伤后，需要FOXF1保持正常的肺形态发生。在AIM I中，我们将使用两种具有FOXF1缺乏症的转基因小鼠系在BPD模型中形成新的肺毛细血管的FOXF1是否需要FOXF1：FOXF1小鼠和TIE2-CRE-FL/FL/FL/FL ER FOXF1小鼠。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模型中内皮细胞存活所必需的。由于我们研究的长期目标是找到可预防人类患者BPD的新型治疗剂，因此在AIM III中，我们将确定新生儿肺中FOXF1水平的提高是否会加速血管形成，增加EC生存率并防止BPD。通过药理学方法（TAT-FOXF1融合蛋白）或遗传方法（内皮细胞中FOXF1的强力霉素诱导的过表达），通过高氧处理的新生小鼠中的FOXF1水平将增加。这些研究的完成将确定升高FOXF1水平是否是预防内皮细胞凋亡并诱导BPD患者血管生成的一种有希望的治疗方法。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且与临床相关的转录调节剂，但其在支气管肺发育不良（BPD）中的作用仍然未知。我们建议使用两个新型的FOXF1缺乏症的小鼠模型，以确定是否需要FOXF1通过刺激血管生成和高氧介导的损伤后内皮细胞（EC）的生存率的增加来维持产后肺形态发生，这是BPD的小鼠模型。我们还建议使用一种新型的治疗剂使用细胞穿透tat-FoxF1融合蛋白来确定新生小鼠中的FOXF1在高氧肺损伤后是否会促进血管修复，减少EC凋亡并预防BPD。