Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
基本信息
- 批准号:10312768
- 负责人:
- 金额:$ 47.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:Automobile DrivingCellsCessation of lifeDataDevelopmentDiseaseDown-RegulationEndotheliumGenesGoalsHistologicHumanIn VitroInterstitial Lung DiseasesLungLung TransplantationLung diseasesMediatingMesenchymalMicroRNAsModelingMolecularMusPatientsPharmaceutical PreparationsPhenotypePre-Clinical ModelPrevalencePrognosisPulmonary FibrosisPulmonary HypertensionPulmonary Vascular ResistanceRattusRefractoryRoleSecondary toTherapeuticUp-RegulationVascular EndotheliumVascular ProliferationVascular remodelingcell typeeffective therapyin vivoinsightknock-downmortalitynew therapeutic targetnovelnovel therapeutic interventionoverexpressionpre-clinicalpreventpulmonary artery endothelial cellpulmonary vascular cellspulmonary vascular disorderpulmonary vascular remodelingslugtargeted treatmenttherapy developmenttranscription factortranscriptome sequencing
项目摘要
Project Summary
Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling,
and death. One of the most common forms of PH is secondary to interstitial lung disease (group 3.2) with a
prevalence of about 30-40% in patients with pulmonary fibrosis (PF). PH development secondary to PF increases
mortality about 3-fold as the combined disease is refractory to most therapies. The lack of effective therapies
can be attributed, at least in part, to the lack of a relevant pre-clinical model of PF-PH. We have developed a
novel pre-clinical rat model of combined PF-PH that recapitulates most of the pathophysiologic findings seen in
patients with PF-PH. We have also identified a novel microRNA, miR125b-3p (miR125b), which is preferentially
and significantly upregulated in the lungs of rats and humans with combined PF-PH compared to PF alone.
miR125 upregulation is associated with significant downregulation of its target TNFAIP3 leading to increased
expression of Slug, a transcription factor responsible for promoting endothelial to mesenchymal transition
(EndMT). Our preliminary data shows overexpression of miR125b in the lungs of rat with pre-existing PF is
sufficient to induce PH and to promote EndMT in human pulmonary artery endothelial cells (HPAECs) in vitro.
The goal of this proposal is to determine how miR125 induces pulmonary vascular remodeling and EndMT to
promote PH in pre-existing PF and to investigate the therapeutic potential of targeting miR125 and Snai2 in
preventing PH in pre-existing PF. Our central hypotheses are: 1) marked increase of miR125b in the lungs
promotes transition of PF to PF-PH by decreasing the expression of its target TNFAIP3 resulting in Snai2
upregulation that stimulates EndMT leading to worsening pulmonary vascular remodeling; and 2) Knock-down
of miR125b and/or Slug in the lungs of rats with pre-existing PF prevents transition from PF to PF-PH. Aim 1 will
gain mechanistic insights into the role of miR125b/Slug axis in promoting PH by driving vascular remodeling in
rats/patients with pre-existing PF; Aim 2 will gain mechanistic insights into the role of miR125b/Slug axis in
promoting PH by driving EndMT in rats/patients with pre-existing PF; and Aim 3 will examine whether miR125b
and/or Slug can serve as novel therapeutic targets to prevent the transition of PF to PF-PH. The proposed studies
will yield important insights into the mechanisms of miR125 overexpression induced PH, thus allowing us to
target miR125 and/or Slug as novel therapeutic strategies to prevent PH.
项目总结
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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Mansoureh Eghbali其他文献
Mansoureh Eghbali的其他文献
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{{ truncateString('Mansoureh Eghbali', 18)}}的其他基金
Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension
肠道炎症在氧化脂质诱导的肺动脉高压中的作用
- 批准号:
10381356 - 财政年份:2022
- 资助金额:
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Role of Chromosome Y gene, Uty, in protecting against Pulmonary Hypertension
Y 染色体基因 Uty 在预防肺动脉高压中的作用
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10310983 - 财政年份:2021
- 资助金额:
$ 47.49万 - 项目类别:
Role of Chromosome Y gene, Uty, in protecting against Pulmonary Hypertension
Y 染色体基因 Uty 在预防肺动脉高压中的作用
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10454301 - 财政年份:2021
- 资助金额:
$ 47.49万 - 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
- 批准号:
10524037 - 财政年份:2019
- 资助金额:
$ 47.49万 - 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
- 批准号:
9917602 - 财政年份:2019
- 资助金额:
$ 47.49万 - 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
- 批准号:
10063562 - 财政年份:2019
- 资助金额:
$ 47.49万 - 项目类别:
Role of miR193 in oxidized lipid induced pulmonary hypertension
miR193在氧化脂质诱导的肺动脉高压中的作用
- 批准号:
9330227 - 财政年份:2016
- 资助金额:
$ 47.49万 - 项目类别:
Role of miR193 in oxidized lipid induced pulmonary hypertension
miR193在氧化脂质诱导的肺动脉高压中的作用
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9107288 - 财政年份:2016
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