Transcriptional Regulation of Endothelial Cells after Acute Lung Injury
急性肺损伤后内皮细胞的转录调控
基本信息
- 批准号:9900064
- 负责人:
- 金额:$ 52.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAdherens JunctionAdultAdult Respiratory Distress SyndromeAllelesAlveolarApplications GrantsBindingBinding SitesBlood VesselsBlood capillariesCapillary Endothelial CellCell CycleCell ProliferationCellsCessation of lifeChIP-seqClinical ManagementComplementComplicationCongenital DisordersCongenital alveolar dysplasiaDataDevelopmentElementsEmbryoEndothelial CellsEndotheliumFOXF1 geneGasesGene ActivationGene ExpressionGenesGenetic TranscriptionHomeostasisHumanHyperoxiaImpairmentIn VitroInflammationInjuryKineticsLaboratoriesLifeLungLung InflammationMAPK8 geneMediatingMediator of activation proteinModelingMolecularMusMutationPatientsPermeabilityPharmacologyPhosphorylationPlayProteinsPulmonary EdemaRattusRegulationRegulatory ElementRepressionRespiratory FailureRoleS PhaseSTAT3 geneSeveritiesSignal TransductionSiteSite-Directed MutagenesisSmall Interfering RNAStat3 proteinStructureTamoxifenTestingTranscriptional RegulationTransgenesTransgenic MiceVascular PermeabilitiesVinculinalpha catenincadherin 5gain of functiongene repressiongenetic approachgenomic locusimprovedin vivoinhibitor/antagonistinjury and repairinnovationknock-downloss of functionlung developmentlung injurylung repairmortalitymouse modelnanoparticleneonatal periodnovelplakoglobinpreventpromoterprotein protein interactionrepairedsmall moleculetranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY. Capillary endothelial cells (ECs) play a key role in alveolar gas exchange and actively
participate in lung repair after acute lung injury (ALI). Acute Respiratory Distress Syndrome (ARDS) is a life-
threatening complication of ALI with high mortality rate. Given the lack of major improvements in ALI/ ARDS
clinical management, there is a compelling need for innovative molecular approaches to complement existing
ALI/ ARDS therapies. My laboratory previously demonstrated that FOXF1 transcription factor is a critical
regulator of lung vascular development in mice and humans. Global deletion of Foxf1 gene in mice is
embryonic lethal, whereas mice heterozygous for the Foxf1 null allele (Foxf1+/-) had reduced numbers of
pulmonary capillaries and increased mortality during the early neonatal period. Inactivating mutations in
FOXF1 gene locus were found in >50% of patients with Alveolar Capillary Dysplasia (ACD), a rare congenital
disorder with high mortality rate due to severe reduction in pulmonary capillaries. While these studies indicate
an important role for FOXF1 in development of pulmonary vasculature, FOXF1 function in adult lung/ injury
repair remains unknown. In this proposal, we provide preliminary data demonstrating that FOXF1 levels are
reduced after lung injury in mice and humans. Endothelial-specific deletion of both Foxf1 alleles causes
respiratory failure and mortality due to loss of endothelial integrity, disruption of adherens junctions and
reduced expression of genes critical for EC barrier function. Deletion of only one Foxf1 allele from ECs inhibits
lung repair and increases mortality in mouse ALI models. Knockdown of FOXF1 in cultured ECs delays cell
entry into S phase, increases levels of cell cycle inhibitors p21cip1 and p15ink4b, and reduces phosphorylation of
STAT3, a key transcriptional mediator of endothelial proliferation. FOXF1 physically binds to the STAT3
protein, and mutations in STAT3-binding region of the FOXF1 protein were recently found in ACD patients,
emphasizing the importance of FOXF1-STAT3 protein interactions in ECs. In this grant proposal, we will
identify molecular mechanisms regulated by FOXF1 during endothelial repair using mouse and rat ALI models.
We will test the hypothesis that FOXF1 promotes lung repair after acute lung injury. In Aim 1, we will use
cultured ECs and unique mouse models with gain-of-function and loss-of-function of FOXF1 to determine the
role of FOXF1 in EC barrier function and identify direct FOXF1 target genes. We will also use nanoparticles
(specifically targeting ECs in vivo) and a small molecule FOXF1-activating compound (recently discovered in
my laboratory) to restore FOXF1 expression after lung injury and determine whether pharmacological targeting
of FOXF1 will promote endothelial repair. In Aim 2, we will examine the importance of FOXF1-STAT3
interactions and FOXF1-mediated repression of p21cip1 and p15ink4b for EC proliferation in vitro and in vivo.
Completion of our studies will identify novel molecular mechanisms whereby FOXF1 regulates lung repair and
determine whether targeting FOXF1 could be beneficial for ALI patients.
项目摘要。毛细管内皮细胞(EC)在肺泡气体交换中起关键作用,并积极地
急性肺损伤(ALI)后参加肺修复。急性呼吸窘迫综合征(ARDS)是一种生命 -
威胁要以高死亡率的ALI并发症。鉴于ALI/ ARDS缺乏重大改进
临床管理,需要创新的分子方法来补充现有的现有
ALI/ ARDS疗法。我的实验室先前证明FOXF1转录因子是关键
小鼠和人类肺血管发育的调节剂。小鼠FOXF1基因的全球删除是
胚胎致死,而FOXF1无效等位基因(FOXF1 +/-)的杂合子的数量减少了
在新生儿初期,肺毛细血管和死亡率增加。灭活突变
在<50%
由于肺毛细血管的严重降低而导致高死亡率的疾病。这些研究表明
FOXF1在肺脉管系统发展中的重要作用,FOXF1在成人肺/损伤中起作用
维修仍然未知。在此建议中,我们提供了初步数据,表明FOXF1级别是
小鼠和人类肺损伤后减少。两个FOXF1等位基因原因的内皮特定删除原因
呼吸衰竭和死亡率由于内皮完整性的丧失,粘附连接处的破坏和
减少对EC屏障功能至关重要的基因表达。从ECS中删除仅删除一个FOXF1等位基因
肺修复并增加了小鼠ALI模型的死亡率。在培养的ECS中敲低FOXF1延迟细胞
进入S相,增加了细胞周期抑制剂的水平P21CIP1和P15INK4B,并降低
STAT3,内皮增殖的关键转录介质。 FOXF1物理与STAT3结合
最近在ACD患者中发现了FOXF1蛋白的Stat3结合区域的蛋白质和突变,
强调FOXF1-STAT3蛋白相互作用在EC中的重要性。在这个赠款建议中,我们将
使用小鼠和大鼠ALI模型在内皮修复过程中识别由FOXF1调节的分子机制。
我们将检验以下假设:FOXF1在急性肺损伤后促进肺修复。在AIM 1中,我们将使用
培养的EC和独特的鼠标模型具有功能获得和FOXF1的功能丧失,以确定
FOXF1在EC屏障功能中的作用并识别直接的FOXF1靶基因。我们还将使用纳米颗粒
(专门针对体内EC)和一个小分子FOXF1激活化合物(最近在
我的实验室)恢复肺损伤后FOXF1表达并确定药理靶向是否
FOXF1的摄入将促进内皮修复。在AIM 2中,我们将研究FOXF1-STAT3的重要性
相互作用和FOXF1介导的P21CIP1和P15INK4B的抑制作用,用于体外和体内EC增殖。
我们研究的完成将确定新型分子机制,FOXF1调节肺修复和
确定靶向FOXF1是否对ALI患者有益。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 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:
$ 52.43万 - 项目类别:
Fox Transcription Factors in Development of Pulmonary Capillaries
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7414733 - 财政年份:2006
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$ 52.43万 - 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:
$ 52.43万 - 项目类别:
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