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:9065597
- 负责人:
- 金额:$ 39万
- 依托单位:
- 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 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAllelesAlveolarAlveolar capillary dysplasia with misalignment of pulmonary veinsBindingBinding ProteinsBirthBlood VesselsBlood capillariesBoxingBronchopulmonary DysplasiaCell ProliferationCellsCongenital DisordersDNA BindingDNA-Binding ProteinsDataDefectDevelopmentDiseaseDominant-Negative MutationEmbryoEndothelial CellsFOXF1 geneFrameshift MutationFunctional disorderFundingGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionHealthHumanHypoxemiaIn VitroInfantInfant MortalityInheritedKDR geneKnock-in MouseLaboratoriesLinkLungLung diseasesMass Spectrum AnalysisMediator of activation proteinModelingMolecularMolecular AbnormalityMorphogenesisMusMutationPathogenesisPatientsPerinatal mortality demographicsPoint MutationProteinsPulmonary veinsRegulationReportingRespiratory InsufficiencyRoleSTAT3 geneSeveritiesSignal TransductionTestingTherapeuticTransgenesTransgenic MiceTransgenic OrganismsVascular Endothelial Growth Factorsangiogenesisbasecapillaryclinically relevanteffective therapyefficacy testinggain of functionimprovedin vivoinsightknock-downloss of functionmigrationmortalitymutantneonatenovelnovel therapeutic interventionpreventpromoterprotein functionprotein protein interactionresearch studysmall moleculetranscription factor
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.
描述(由申请方提供):肺泡毛细血管发育不良伴肺静脉错位(ACD/MPV)是一种新生儿和婴儿致命的先天性疾病,由肺血管发育严重缺陷引起。由于ACD/MPV婴儿发育缺陷和进行性呼吸功能不全的严重性,死亡通常发生在出生后的第一个月内。ACD/MPV患者尚无有效的治疗方法,迫切需要新的治疗方法。最近,在40%的ACD/MPV病例中发现了叉头盒F1(FOXF 1)基因的显性遗传杂合突变。我的实验室先前证明FOXF 1转录因子是肺血管发育的关键调节因子。小鼠Foxf 1基因的整体缺失是胚胎致死性的,而Foxf 1-null等位基因(Foxf 1 +/-)杂合小鼠的肺毛细血管数量减少,肺发育不全和围产期死亡率增加,这些都是人类ACD/MPV的关键特征。在之前的资助期间,我们产生了内皮特异性缺失Foxf 1的小鼠,并证明FOXF 1以细胞自主方式调节肺内皮细胞中的血管生成和VEGF信号传导。虽然有42种不同的FOXF 1突变与ACD/MPV有关,但这些突变干扰肺形态发生和功能的分子机制仍不清楚。我们将集中在五个不同的FOXF 1突变,可能有不同的发病机制,在ACD/MPV。我们的假设是FOXF 1突变通过抑制DNA结合(S52 F和G91 E突变)、干扰野生型(WT)FOXF 1蛋白(Del 872 -879)的功能或灭活STAT 3信号传导(Y284 A和I285 Q)来破坏肺血管发育。在目标1中,我们将FOXF 1突变引入原代肺内皮细胞,以确定这些突变破坏细胞增殖,迁移和血管生成的分子机制。我们还将产生表达一个WT Foxf 1等位基因和一个突变Foxf 1等位基因的敲入小鼠,模拟ACD/MPV患者的遗传异常。我们将使用这些小鼠来鉴定FOXF 1突变扰乱肺形态发生和功能的分子机制。我们还将使用一种新的小分子化合物,其稳定WT FOXF 1蛋白,以刺激肺血管的发育并提高小鼠ACD模型的存活率。在目标2中,使用质谱,我们已经发现FOXF 1直接结合到STAT 3蛋白,这是内皮细胞的关键转录调节因子。因此,我们将确定FOXF 1是否作为STAT 3的共激活剂来诱导STAT 3信号传导。我们还将测试通过Y284 A和I285 Q FOXF 1突变破坏FOXF 1-STAT 3相互作用是否损害体内肺血管发育。总而言之,由于在几种肺部疾病中已经报道了FOXF 1和STAT 3的减少,因此最近在我的实验室中鉴定的FOXF 1稳定化合物可能具有广泛的治疗应用,用于治疗目前无法治愈的ACD/MPV和其他与血管功能不全相关的肺部疾病。
项目成果
期刊论文数量(0)
专著数量(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:
10170416 - 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:
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
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$ 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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