Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
基本信息
- 批准号:10881631
- 负责人:
- 金额:--
- 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:2019-07-01 至 2024-09-30
- 项目状态:已结题
- 来源:
- 关键词:AffectApoptosisApoptoticAutophagocytosisBinding SitesBiologicalBiologyBlood flowCell ProliferationCell SeparationChronicChronic Obstructive Pulmonary DiseaseChronic lung diseaseComplicationCoupledCyclic AMP-Responsive DNA-Binding ProteinDataDetectionDevelopmentDiseaseExhibitsExposure toGeneticGenetic TranscriptionGenus HippocampusGlycolysisGoalsHospital CostsHospitalizationHumanHypoxemiaHypoxiaImaging TechniquesImpairmentIn VitroLength of StayLuciferasesLungLung diseasesMediatingMetabolicMetabolismMicroRNAsMitochondriaMolecularMorbidity - disease rateMusOxygen ConsumptionPINK1 genePTEN genePathogenesisPathogenicityPathway interactionsPatientsPhenotypePhosphotransferasesPost-Transcriptional RegulationPredispositionProliferatingProteinsPulmonary HypertensionPulmonary artery structureQuality ControlRattusRegulationReporterReportingResearchResearch Project GrantsRespirationRiskRodentRodent ModelRoleSignal TransductionSmooth Muscle MyocytesSourceStructure of parenchyma of lungTalentsTechniquesTestingTherapeuticTissuesTransfectionTransgenic MiceTransgenic OrganismsTumor Suppressor ProteinsVascular DiseasesVascular remodelingVeteransWorkbioinformatics toolcancer cellcellular imagingcomorbiditydifferential expressiondiminished oxidative phosphorylationdisease prognosisexercise capacityexposed human populationfunctional improvementgain of functionhuman tissuehypoxia-induced pulmonary hypertensionimprovedin silicoin vivoinnovationinsightloss of functionlung hypoxiamilitary veteranmitochondrial dysfunctionmortalityneuroblastoma cellnew therapeutic targetnovelnovel therapeutic interventionposttranscriptionalpromoterpulmonary arterial hypertensionreduce symptomsright ventricular failuresmoking-related lung diseasetranscription factortranslational impactvector
项目摘要
Pulmonary hypertension (PH) is a progressive disorder associated with a variety of diseases commonly
afflicting veteran patients. Emerging evidence demonstrates that PH and excessive proliferation of pulmonary
artery smooth muscle cells (PASMC) are caused by derangements in mitochondrial function that impair
mitochondrial respiration and alter mitochondrial metabolic programming in a manner that enhances glycolytic
metabolism and diminishes oxidative phosphorylation. However, abnormalities in mitochondrial quality control
mechanisms that regulate mitophagy have not been investigated as a source of mitochondrial dysfunction and
PASMC hyperproliferation in PH, and will be explored in detail in the proposed studies.
The proposed studies will investigate the role of the mitophagy initiator protein, PTEN-induced putative
kinase-1 (PINK1) in the pathogenesis of PH and PASMC proliferation. Our preliminary data demonstrate that
PINK1 is reduced in hypoxia-exposed PASMC in vitro and in the lungs and pulmonary artery tissues of rodents
that develop PH in hypoxic conditions. In the proposed studies, we will investigate the hypothesis that loss of
PINK1 causes impairments in mitophagy and mitochondrial metabolic programming that lead to
excessive PASMC proliferation in PH. Additional studies will define the mechanisms that regulate PINK1
loss in hypoxic conditions. We will test our hypothesis through the execution of the following Specific Aims:
Aim 1 will investigate transcriptional and posttranscriptional mechanisms that regulate PINK1 through
microRNA (miR). Among several miRs identified by in silico analysis, miR-27a and miR-516a exhibited the
greatest differential expression changes in the hypoxic rodent lung and in hypoxic PASMC. Therefore, initial
studies will determine if PINK1 loss occurs through miR-27a- or miR-516a-mediated posttranscriptional
suppression of PINK1. To identify factors that regulate PINK1 transcription, we employed bioinformatics tools
to define predicted transcription factor (TF) binding sites in the PINK1 promoter. Among several TFs identified,
regulatory interactions between cAMP response element-binding protein (CREB) and PINK1 had not been
previously validated. Therefore, we will conduct studies using a PINK1 promoter luciferase reporter vector to
determine whether putative CREB binding sites are functional. To enhance the translational impact, we will
determine mechanisms that regulate PINK1 expression and activity using idiopathic pulmonary artery
hypertension (IPAH) PASMC and lung tissue.
Aim 2 will characterize the functional consequences of PINK1 alterations on mitochondrial metabolic
reprogramming, mitophagy, and PASMC proliferation in PH. In isolated rat PASMC, the impact of hypoxia or
PINK1 gain and loss of function on mitochondrial oxygen consumption and glycolysis will be analyzed using
the Seahorse XF96 Bioanalyzer™. Additional studies will determine the effects of hypoxia or PINK1 alterations
on mitophagy in the lung in vivo using Mt-Keima transgenic mice and in PASMC isolated from rats and IPAH
donors using the mKeima-Red® mitophagy detection vector in vitro.
The fundamental goals of this proposal are to provide novel insights into aspects of mitochondrial
dysfunction in PH that contribute to PASMC hyperproliferation and PH through alterations in PINK1 and
mitophagy. The successful execution of this work will broaden our understanding of the role of mitophagy in
PH and lay the groundwork to investigate novel therapies that target PINK1.
肺动脉高压(pulmonary hypertension,PH)是一种进行性疾病,常与多种疾病相关
折磨着退伍军人患者新出现的证据表明,PH和过度增殖的肺
动脉平滑肌细胞(PASMC)是由线粒体功能紊乱引起的,
线粒体呼吸并以增强糖酵解的方式改变线粒体代谢程序
代谢和减少氧化磷酸化。然而,线粒体质量控制的异常
调节线粒体自噬的机制尚未被研究为线粒体功能障碍的来源,
PH中PASMC过度增殖,并将在拟定研究中详细探讨。
这项研究将探讨线粒体自噬起始蛋白、PTEN诱导的假定的线粒体自噬蛋白在细胞凋亡中的作用。
PINK 1在PH和PASMC增殖的发病机制中的作用。我们的初步数据表明,
PINK 1在体外低氧暴露的PASMC和啮齿动物的肺和肺动脉组织中减少
在缺氧条件下会产生PH值。在拟议的研究中,我们将调查的假设,损失的
PINK 1导致线粒体自噬和线粒体代谢程序的损伤,导致
进一步的研究将确定PINK 1的调控机制
缺氧条件下的损失。我们将通过执行以下具体目标来检验我们的假设:
目的1将研究转录和转录后机制,调节PINK 1,通过
microRNA(miR)。在通过计算机模拟分析鉴定的几种miR中,miR-27 a和miR-516 a表现出
在缺氧啮齿动物肺和缺氧PASMC中差异表达变化最大。因此,初始
研究将确定PINK 1丢失是否通过miR-27 a或miR-516 a介导的转录后
抑制PINK 1。为了确定调控PINK 1转录的因子,我们采用生物信息学工具,
以确定PINK 1启动子中预测的转录因子(TF)结合位点。在几个确定的TF中,
cAMP反应元件结合蛋白(CREB)和PINK 1之间的调节相互作用尚未被证实。
以前验证过。因此,我们将使用PINK 1启动子荧光素酶报告载体进行研究,
确定假定的CREB结合位点是否有功能。为了提高翻译的影响力,我们将
利用特发性肺动脉确定调节PINK 1表达和活性的机制
高血压(IPAH)PASMC和肺组织。
目的2将描述PINK 1改变对线粒体代谢的功能后果,
在分离的大鼠PASMC中,缺氧或缺氧对PASMC增殖的影响,
PINK 1在线粒体耗氧量和糖酵解方面的功能获得和丧失将使用
Seahorse XF96 Bioanalyzer™。进一步的研究将确定缺氧或PINK 1改变的影响。
使用Mt-Keima转基因小鼠体内肺中以及从大鼠和IPAH分离的PASMC中的线粒体自噬
在体外使用mKeima-Red®线粒体自噬检测载体检测供体。
这项提案的基本目标是提供新的见解方面的线粒体
PH功能障碍,通过PINK 1的改变导致PASMC过度增殖和PH,
线粒体自噬这项工作的成功执行将扩大我们对线粒体自噬在以下方面作用的理解:
PH,并为研究针对PINK 1的新疗法奠定基础。
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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C MICHAEL HART其他文献
C MICHAEL HART的其他文献
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{{ truncateString('C MICHAEL HART', 18)}}的其他基金
Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
- 批准号:
9974277 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
- 批准号:
10266041 - 财政年份:2019
- 资助金额:
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Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
肺动脉高压中 PPAR γ 减少的机制和后果
- 批准号:
8440548 - 财政年份:2012
- 资助金额:
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Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
肺动脉高压中 PPAR γ 减少的机制和后果
- 批准号:
8598800 - 财政年份:2012
- 资助金额:
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8402582 - 财政年份:2011
- 资助金额:
-- - 项目类别:
PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8963181 - 财政年份:2011
- 资助金额:
-- - 项目类别:
PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8207904 - 财政年份:2011
- 资助金额:
-- - 项目类别:
PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8598927 - 财政年份:2011
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PPAR gamma and Nox4 in pulmonary hypertension
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