Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia
开发治疗肺泡毛细血管发育不良的新疗法
基本信息
- 批准号:10895101
- 负责人:
- 金额:$ 53.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:ACVRL1 geneAllelesAlveolarAlveolar capillary dysplasia with misalignment of pulmonary veinsApplications GrantsBirthBlood CirculationBlood VesselsBlood capillariesBronchopulmonary DysplasiaCell LineageCell ProliferationCell TherapyCell TransplantationCellsComplementary DNACongenital DisordersCongenital alveolar dysplasiaCyanosisDataDevelopmentDiaphragmatic HerniaDiffuseDiseaseDonor personEmbryoEndothelial CellsEndotheliumEngraftmentExhibitsFOXF1 geneGene DeliveryGenesGenetic TranscriptionHemorrhageHeterogeneityHeterozygoteHumanIn VitroInfantInheritedLaboratoriesLifeLinkLoxP-flanked alleleLungLung TransplantationModelingMusMutationNeonatalNewborn InfantPECAM1 genePTPRC genePathologicPathway interactionsPatientsPrognosisProliferatingProtocols documentationPublishingPulmonary CirculationPulmonary veinsResistanceRespiratory FailureRespiratory InsufficiencyRespiratory physiologySTAT3 geneSignal PathwaySignal TransductionStem cell transplantTEK geneTestingTherapeuticTransgenic MiceVascular Endothelial Growth Factorsangiogenesisbone morphogenetic protein 9c-myc Genesclinically relevantdensitydirected differentiationeffective therapyembryonic stem cellendothelial stem cellexpression vectorfibrotic lunggene delivery systemgenomic locushuman embryonic stem cellimprovedin vivoinnovationlung developmentmortalitymouse modelnanoparticlenanoparticle deliveryneonatenovelnovel therapeutic interventionpostnatalpreservationpreventpulmonary arterial hypertensionrespiratoryself-renewalsingle-cell RNA sequencingtranscription factor
项目摘要
PROJECT SUMMARY. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a
fatal congenital disorder of neonates and infants which leads to respiratory insufficiency due to reduced
numbers of alveolar capillaries and is associated with lung hypoplasia, hemorrhage, malposition of pulmonary
veins and pulmonary arterial hypertension (PAH). ACDMPV is linked to mutations in the Forkhead Box F1
(FOXF1) gene and is resistant to all available therapies and respiratory support, causing cyanosis and
respiratory failure in the first month after birth. In rare cases, ACDMPV patients survive several months or even
years, but they require lung transplantation early in life. Given the lack of effective treatments for ACDMPV,
there is an urgent need for innovative therapeutic approaches to stimulate pulmonary angiogenesis and
preserve respiratory function in ACDMPV infants. In our preliminary data, we have generated a clinically
relevant model of ACDMPV by introducing the S52F FOXF1 mutation (found in ACDMPV patients) into the
endogenous mouse Foxf1 gene locus. Foxf1WT/S52F newborn mice exhibited alveolar capillary dysplasia,
misalignment of pulmonary veins, PAH, and increased mortality, all key features of human ACDMPV.
Endothelial proliferation and STAT3 signaling were decreased in Foxf1WT/S52F mice and human ACDMPV
lungs. In the present grant application, we will test the hypothesis that increasing neonatal lung angiogenesis
will decrease PAH, improve survival and prevent lung remodeling in mouse ACDMPV models. In Aim 1, we
have developed a novel nanoparticle gene delivery system targeting >85% of pulmonary endothelial cells in
vivo when delivered into the neonatal blood circulation. Nanoparticle delivery of STAT3 cDNA after birth
induced endothelial proliferation and increased alveolar microvascular density in Foxf1WT/S52F neonatal lungs.
We will use two mouse models of ACDMPV (Foxf1WT/S52F and Foxf1+/-) to test whether nanoparticle delivery of
STAT3 or FOXF1 will decrease PAH, improve survival and prevent lung remodeling. We will also determine
whether the FOXF1/STAT3/cMYC transcriptional cascade is required for neonatal lung angiogenesis. In Aim
2, we provided preliminary data demonstrating that a cell transplantation with pulmonary endothelial progenitor
cells (EPCs) (FOXF1+cKit+CD31+CD45-) increases the capillary density in Foxf1WT/S52F lungs. We will
investigate heterogeneity of pulmonary EPCs and test their therapeutic potential in mouse ACDMPV models.
We will test if EPCs stimulate neonatal lung angiogenesis via the BMP-9/ACVRL1 signaling pathway. Finally,
we will use a novel protocol for in vitro differentiation of EPCs from mouse and human embryonic stem cells
(ES) and determine if a cell therapy with ES-derived EPCs will be beneficial in mouse ACDMPV models.
Altogether, the proposed studies will directly test whether endothelial delivery of STAT3 or cell therapy with
EPCs have therapeutic potential in ACDMPV.
项目总结。肺泡毛细血管发育不良伴肺静脉错位(ACDMPV)
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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Tanya Kalin其他文献
Tanya Kalin的其他文献
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{{ truncateString('Tanya Kalin', 18)}}的其他基金
Role of lung endothelial cells during fibrotic lung remodeling.
肺内皮细胞在纤维化肺重塑中的作用。
- 批准号:
10275717 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia
开发治疗肺泡毛细血管发育不良的新疗法
- 批准号:
10395588 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Role of lung endothelial cells during fibrotic lung remodeling.
肺内皮细胞在纤维化肺重塑中的作用。
- 批准号:
10646265 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia
开发治疗肺泡毛细血管发育不良的新疗法
- 批准号:
10579232 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia
开发治疗肺泡毛细血管发育不良的新疗法
- 批准号:
10218489 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Role of lung endothelial cells during fibrotic lung remodeling
肺内皮细胞在纤维化肺重塑中的作用
- 批准号:
10931822 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Role of lung endothelial cells during fibrotic lung remodeling.
肺内皮细胞在纤维化肺重塑中的作用。
- 批准号:
10435583 - 财政年份:2021
- 资助金额:
$ 53.16万 - 项目类别:
Role of Foxm1 in Lung Cancer Microenvironment
Foxm1在肺癌微环境中的作用
- 批准号:
8295951 - 财政年份:2010
- 资助金额:
$ 53.16万 - 项目类别:
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