Mechanisms of Prostacyclin signaling in Pulmonary Arterial Hypertension
肺动脉高压中前列环素信号传导机制
基本信息
- 批准号:7662797
- 负责人:
- 金额:$ 22.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectBiological ModelsBlood VesselsCellsChromosomal LossCpG IslandsDataDevelopmentDiseaseDown-RegulationEffectivenessEndothelial CellsEndothelinEnzymesEpigenetic ProcessEpoprostenolEpoprostenol ReceptorsFluorescent in Situ HybridizationFrequenciesGene ExpressionGenesGeneticGenetic PolymorphismHaplotypesHumanHypertrophyHypoxiaInstructionLengthLesionLoss of HeterozygosityLungMediatingMembraneMethylationMinisatellite RepeatsModelingMorbidity - disease rateMusNuclearNuclear ReceptorsOnset of illnessOutcomePathologyPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPersonsPopulationPredispositionPromoter RegionsProstacyclin synthaseProstaglandins IPublishingPulmonary HypertensionPulmonary artery structureRelative (related person)RoleSeveritiesSeverity of illnessSignal TransductionSingle Nucleotide PolymorphismSmooth MuscleTransactivationTransgenic MiceTranslatingVariantVascular remodelingWorkanalogcell growthcell typedisorder preventionhuman diseasehypertension treatmentimprovedinhibitor/antagonistmouse modelnovelphosphodiesterase Vpre-clinicalpressureprimary pulmonary hypertensionprogesterone 11-hemisuccinate-(2-iodohistamine)promoterpulmonary arterial hypertensionreceptor
项目摘要
Pulmonary Arterial Hypertension (PAH) is characterized by elevations in pulmonary artery pressure,vascular
remodeling, and hyperproliferation of endothelial cells. While there is no cure or prevention for this disease,
newer targetedtherapies can improve outcomes by altering vascular tone using prostacyclin (PGI2)
analogues, dual endothelin antagonists, or phosphodiesterase - 5 inhibitors. Recent progress inthe
understanding of genetic aberrations in PAH suggests that modifier genes are potentially involved in
mediating increased susceptibility and severity. Two genes that affect the level of prostacyclin signaling,
prostacyclin synthase (PGIS) and the nuclear receptor PPARy, are down-regulated in patients with PAH.
Disruption of PGI2 signaling through the PPARy pathway leads to aberrant cell growth. Our hypothesis
proposes that PGI2 can signal through either PGIR or PPARy. We hypothesize that signaling through PGIR
results in more prominent effects on vascular tone while PPARy stimulation results in effects onvascular
remodeling. This proposal focuses on 1) the effectiveness of augmenting signaling through the two different
PGI2 receptors as a treatment to reverse remodeling of both smooth muscle and endothelial cells in PAH
(PPARY) or vascular tone (PGIR), 2) the potential modifier gene role of the PGIS and gene in conferring a
predisposition to PAH and an increased likelihood of developing severe PAH,and 3) the mechanism of PGIS
and PPARy loss of expression in human disease. We will use two sophisticated murine modeling systems
generated by our group to dissect the relative contribution of the two receptors to the development of PAH.
Our preliminary work demonstrates that sequence variation in the proximal PGIS promoter region affects
promoter activity leading to low PGIS expression. We will sequence the PGIS promoters from familial
pulmonary hypertension, correlating specific haplotypes with disease on-set, severity, and morbidity. Finally,
because epigenetic silencing and chromosomal loss are common mechanisms of gene expression down-
regulation, we will determine if either is responsible for PGIS or PPARy down-regulation in micro-dissected
PAH lesions using methylation specific PCR (MSP) and fluorescence in situ hybridization (FISH). Specific
Aim 1: Delineate the contributions of PGIS and PPARy pathwaysto PAH susceptibility and severity. Specific
Aim 2: Define transcriptional activity of PGIS promoter sequence variations in relevant primary cells types,
and their frequency and correlation in a defined human population. Specific Aim 3: Determine if methylation
silencing and/or allelic loss account for PGIS and PPARy down-regulation.
RELEVANCE (See instructions):
We have previously demonstrated that two critical modulators of vascular tone and proliferation (PGI2 and
PPAR-/) are downregulated in disease. This application utilizes translational murine modeling to examine
mechanisms of signaling important to vasculartone and remodeling. Furthermore, studies of patients with
the PAH will be performed to examine the relationship of genetic polymorphisms and disease severity, as
well as mechanisms of loss of PGI2 and PPARy.
肺动脉高压(PAH)的特征在于肺动脉压力、血管压力和肺动脉压力的升高。
重塑和内皮细胞过度增殖。虽然没有治愈或预防这种疾病,
新的靶向治疗可以通过使用前列环素(PGI 2)改变血管张力来改善预后
类似物、双重内皮素拮抗剂或磷酸二酯酶-5抑制剂。最近的进展
对PAH中遗传畸变的理解表明,修饰基因可能参与了PAH的发生,
介导增加的易感性和严重性。两个影响前列环素信号水平的基因,
前列环素合酶(PGIS)和核受体PPARy在PAH患者中下调。
通过PPARy途径破坏PGI 2信号传导导致异常细胞生长。我们的假设
提出PGI 2可以通过PGIR或PPARy发出信号。我们假设通过PGIR的信号传导
导致对血管张力的更显著的作用,而PPARy刺激导致对血管张力的作用,
重塑该提议集中于1)通过两种不同的通信协议增强信令的有效性。
PGI 2受体作为逆转PAH中平滑肌和内皮细胞重塑的治疗
(PPARY)或血管张力(PGIR),2)PGIS和基因在赋予血管张力(PPARY)或血管张力(PGIR)中的潜在修饰基因作用,
PAH易感性和发生重度PAH的可能性增加,以及3)PGIS的机制
和人疾病中的PPARy表达缺失。我们将使用两个复杂的小鼠建模系统
我们的小组所产生的,以解剖的相对贡献的两个受体的发展PAH。
我们的初步工作表明,近端PGIS启动子区的序列变异影响了PGIS基因的表达。
启动子活性导致低PGIS表达。我们将对家族性PGIS启动子进行测序,
肺动脉高压,将特定单倍型与疾病发作、严重程度和发病率相关联。最后,
因为表观遗传沉默和染色体丢失是基因表达下调的常见机制,
调节,我们将确定是否负责PGIS或PPARy下调在显微解剖的
使用甲基化特异性PCR(MSP)和荧光原位杂交(FISH)检测PAH病变。具体
目的1:阐明PGIS和PPARy通路对PAH易感性和严重程度的作用。具体
目的2:确定PGIS启动子序列变异在相关原代细胞类型中的转录活性,
以及它们在特定人群中的频率和相关性。具体目标3:确定甲基化是否
沉默和/或等位基因丢失导致PGIS和PPARy下调。
相关性(参见说明):
我们以前已经证明了血管张力和增殖的两个关键调节剂(PGI 2和PGI 3),
PPAR-1)在疾病中下调。本申请利用翻译鼠模型来检查
对血管紧张素和重塑重要的信号传导机制。此外,对患有
将进行PAH检查,以检查遗传多态性与疾病严重程度的关系,
以及PGI 2和PPARy的丢失机制。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARK W GERACI其他文献
MARK W GERACI的其他文献
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{{ truncateString('MARK W GERACI', 18)}}的其他基金
Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
- 批准号:
8320228 - 财政年份:2011
- 资助金额:
$ 22.57万 - 项目类别:
Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
- 批准号:
8490706 - 财政年份:2011
- 资助金额:
$ 22.57万 - 项目类别:
Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
- 批准号:
8097154 - 财政年份:2011
- 资助金额:
$ 22.57万 - 项目类别:
53rd Annual Thomas L Petty Aspen Lung Conference: Systems Biology of Lung Disease
第 53 届 Thomas L Petty Aspen 肺病年度会议:肺部疾病的系统生物学
- 批准号:
8005685 - 财政年份:2010
- 资助金额:
$ 22.57万 - 项目类别:
Prostacyclin Synthase and Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的前列环素合酶和受体
- 批准号:
7824361 - 财政年份:2009
- 资助金额:
$ 22.57万 - 项目类别:
Molecular Physiology Core Applied to Acute Lung Injury
分子生理学核心应用于急性肺损伤
- 批准号:
7936177 - 财政年份:2009
- 资助金额:
$ 22.57万 - 项目类别:
Molecular Physiology Core Applied to Acute Lung Injury
分子生理学核心应用于急性肺损伤
- 批准号:
7859480 - 财政年份:2009
- 资助金额:
$ 22.57万 - 项目类别:
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