Pulmonary Vascular-Right Ventricular Axis Research Program

肺血管-右心室轴研究计划

基本信息

  • 批准号:
    8530275
  • 负责人:
  • 金额:
    $ 62.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-15 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and vascular growth; right ventricular failure is the leading cause of death. Our studies have identified loss of pulmonary vascular endothelial nitric oxide synthase (eNOS) activity in PAH, and that the NO deficiency leads to hypoxia-inducible factor-1 (HIF-1) activation, which results in glycolytic, proliferative, apoptosis-resistant endothelial cells that promote vascular remodeling. The mechanism(s) of eNOS activity loss is unknown. eNOS is also present in the cardiomyocyte, where NO synthesis by eNOS is cardioprotective; but eNOS has not been studied in the human PAH heart. Activation of eNOS requires enzyme dephosphorylation at Threonine 495 (T495) and phosphorylation at Serine 1177 (S1177), the latter mediated by cyclic adenosine monophosphate (cAMP)/protein kinase pathways downstream of ?-Adrenergic Receptors (?AR) [Fig 1]. Because ?AR downregulation and desensitization are found in all heart failure, we investigated ?AR in the eNOS activity loss and its consequences on the pulmonary vascular-right ventricular (RV) axis. Explanted human PAH hearts have desensitization and low numbers of ?AR, and for the first time, we show that pulmonary arterial endothelial cells (PAEC) from human PAH lungs have similarly low numbers and de- sensitization of ?AR. Preliminary data reveal that ?AR desensitization is due to deficient dephosphorylation of the receptor by phosphatases, which are inhibited by over-activation of phosphatidyl inositol 3-kinase (PI3Kg). ?AR numbers are low due to defective intracellular recycling of phosphorylated receptors. Consistent with PI3K inhibition of phosphatases, PAH PAEC and cardiomyocytes have high levels of the inactive pT495 eNOS, identifying the cause of decreased NO production upon any type of agonist stimulation, i.e. eNOS is in an inactive state. As in the endothelial cell, NO deficiency in PAH hearts is associated with greater HIF-activation and increased glycolytic metabolism as identified by glycolytic enzyme expression and uptake of the glucose analogue [18F]2-fluoro-2-deoxy-D-glucose by positron emission tomography (fasting FDG-PET) in PAH patients. Exciting preliminary studies indicate that b-blockers reverse ?AR dysfunction, restore phosphatase- mediated eNOS activation, and thus increase cAMP and NO production, respectively. Thus, we hypothesize that cardiomyocytes and endothelial cells in PAH suffer from interconnected abnormalities of ?AR function and eNOS activation that lead to a HIF-mediated maladaptive vascular and cardiomyocyte phenotype, all of which is reversible by ?-blocker. We test this hypothesis PAEC derived from patients' lungs, explanted human hearts, and in a mechanistic longitudinal study of ?AR blockade in PAH patients.
描述(申请人提供):肺动脉高压(PAH)是一种致命的疾病,其特征是肺血流动力学和血管生长调节受损;右心衰竭是主要的死亡原因。我们的研究证实,PAH时肺血管内皮型一氧化氮合酶(ENOS)活性丧失,NO缺乏导致缺氧诱导因子-1(HIF-1)激活,从而导致糖酵解、增殖、抗凋亡的内皮细胞促进血管重塑。ENOS活性丧失的机制(S)尚不清楚。ENOS也存在于心肌细胞中,在心肌细胞中,eNOS的合成不具有心脏保护作用;但eNOS在人类PAH心脏中尚未被研究。ENOS的激活需要苏氨酸495(T495)和丝氨酸1177(S1177)的酶去磷酸化,后者由β-肾上腺素能受体(?AR)下游的环磷酸腺苷(CAMP)/蛋白激酶通路介导[图1]。由于?AR下调和脱敏在所有心力衰竭中都被发现,我们研究了?AR在eNOS活性丧失中的作用及其对肺血管-右室(RV)轴的影响。移植的人PAH心脏具有脱敏和低数量的?AR,我们首次发现来自人PAH肺的肺动脉内皮细胞(PAEC)具有同样的低数量和对?AR的脱敏。初步数据表明,AR脱敏是由于磷脂酰肌醇3-激酶(PI3Kg)过度激活抑制的磷酸酶对受体的去磷酸化作用。?AR数低是由于磷酸化受体在细胞内的循环有缺陷。与PI3K抑制磷酸酶一致,PAH PAEC和心肌细胞有高水平的非活性pT495 eNOS,确定了在任何类型的激动剂刺激下NO产生减少的原因,即eNOS处于非活动状态。与内皮细胞一样,PAH患者心脏中的NO缺乏与更大的HIF激活和糖酵解代谢增加有关,这是通过PAH患者的糖酵解酶表达和摄取葡萄糖类似物[18F]2-氟-2-脱氧-D-葡萄糖(空腹FDG-PET)来确定的。令人兴奋的初步研究表明,b-受体阻滞剂逆转AR功能障碍,恢复磷酸酶介导的eNOS激活,从而分别增加cAMP和NO的产生。因此,我们假设PAH中的心肌细胞和血管内皮细胞存在?AR功能和eNOS激活的相互关联的异常,导致HIF介导的血管和心肌细胞表型异常,所有这些都是被?-受体阻滞剂逆转的。我们验证了这一假设,PAEC来源于患者的肺、移植的人的心脏,并在一项对PAH患者的?AR阻断的机械性纵向研究中。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Serpil C. Erzurum其他文献

DEFINITION, PREVALENCE AND PATHOPHYSIOLOGIC ROLE OF IRON DEFICIENCY IN PULMONARY VASCULAR DISEASE
  • DOI:
    10.1016/s0735-1097(23)02335-5
  • 发表时间:
    2023-03-07
  • 期刊:
  • 影响因子:
  • 作者:
    Pieter Martens;Shilin Yu;Samar Farha;Serpil C. Erzurum;Anna Hemnes;Evelyn M. Horn;Franz Rischard;Erika Rosenzweig;Margaret M. Park;Paul Hassoun;Wai Hong Wilson Tang
  • 通讯作者:
    Wai Hong Wilson Tang
Clinical Implications of Pretest Probability of HFpEF on Outcomes in Precapillary Pulmonary Hypertension
射血分数保留的心力衰竭(HFpEF)的预测试概率对毛细血管前性肺动脉高压预后的临床意义
  • DOI:
    10.1016/j.jacc.2024.08.061
  • 发表时间:
    2024-11-26
  • 期刊:
  • 影响因子:
    22.300
  • 作者:
    Yogesh N.V. Reddy;Robert P. Frantz;Paul M. Hassoun;Anna R. Hemnes;Evelyn Horn;Jane A. Leopold;Franz Rischard;Erika B. Rosenzweig;Nicholas S. Hill;Serpil C. Erzurum;Gerald J. Beck;J. Emanuel Finet;Christine L. Jellis;Stephen C. Mathai;W.H. Wilson Tang;Barry A. Borlaug
  • 通讯作者:
    Barry A. Borlaug
IMPAIRED GLOBAL RIGHT VENTRICULAR LONGITUDINAL STRAIN PREDICTS LONG-TERM ADVERSE OUTCOMES IN PATIENTS WITH PRIMARY PULMONARY HYPERTENSION
  • DOI:
    10.1016/s0735-1097(12)61595-2
  • 发表时间:
    2012-03-27
  • 期刊:
  • 影响因子:
  • 作者:
    Jae-Hyeong Park;Margaret Park;Samar Farha;Jacqueline Sharp;Erika Lundgrin;Suzy Comhair;Wai Hong Tang;Serpil C. Erzurum;James Thomas
  • 通讯作者:
    James Thomas
Kolorado Üniversitesi Tip Fakültesi, Tip Bölümü, Translasyonel Akciğer Araştirma Programi, Aurora, Kolorado, ABD;
Kolorado Üniversitesi Tip Fakültesi、Tip Bölümü、Translasyonel Akciğer Araştirma Programi、Aurora、Kolorado、ABD;
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Rubin M. Tuder;Stephen L. Archer;Peter Dorfmüller;Serpil C. Erzurum;Christophe Guignabert;Evangelos D. Michelakis;Marlene Rabinovitch;Ralph T. Schermuly;Kurt R. Stenmark;NW Morrell
  • 通讯作者:
    NW Morrell
Disentangling the Impact of Adiposity From Insulin Resistance in Heart Failure With Preserved Ejection Fraction
在射血分数保留型心力衰竭中区分肥胖与胰岛素抵抗的影响
  • DOI:
    10.1016/j.jacc.2025.03.530
  • 发表时间:
    2025-05-13
  • 期刊:
  • 影响因子:
    22.300
  • 作者:
    Yogesh N.V. Reddy;Robert P. Frantz;Anna R. Hemnes;Paul M. Hassoun;Evelyn Horn;Jane A. Leopold;Franz Rischard;Erika B. Rosenzweig;Nicholas S. Hill;Serpil C. Erzurum;Gerald J. Beck;J. Emanuel Finet;Christine L. Jellis;Stephen C. Mathai;W.H. Wilson Tang;Barry A. Borlaug;PVDOMICS Study Group
  • 通讯作者:
    PVDOMICS Study Group

Serpil C. Erzurum的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Serpil C. Erzurum', 18)}}的其他基金

Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network (UG1)
NHLBI 重度和/或易加重哮喘的精准干预临床中心 (PrecISE) 网络 (UG1)
  • 批准号:
    9406651
  • 财政年份:
    2017
  • 资助金额:
    $ 62.79万
  • 项目类别:
Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network (UG1)
NHLBI 重度和/或易加重哮喘的精准干预临床中心 (PrecISE) 网络 (UG1)
  • 批准号:
    10221036
  • 财政年份:
    2017
  • 资助金额:
    $ 62.79万
  • 项目类别:
Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network (UG1)
NHLBI 重度和/或易加重哮喘的精准干预临床中心 (PrecISE) 网络 (UG1)
  • 批准号:
    10455086
  • 财政年份:
    2017
  • 资助金额:
    $ 62.79万
  • 项目类别:
Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network (UG1)
NHLBI 重度和/或易加重哮喘精准干预临床中心 (PrecISE) 网络 (UG1)
  • 批准号:
    10006108
  • 财政年份:
    2017
  • 资助金额:
    $ 62.79万
  • 项目类别:
Pulmonary Hypertension Breakthrough Initiative
肺动脉高压突破计划
  • 批准号:
    9103243
  • 财政年份:
    2015
  • 资助金额:
    $ 62.79万
  • 项目类别:
Pulmonary Hypertension Breakthrough Initiative
肺动脉高压突破计划
  • 批准号:
    8756641
  • 财政年份:
    2014
  • 资助金额:
    $ 62.79万
  • 项目类别:
Pulmonary Vascular-Right Ventricular Axis Research Program
肺血管-右心室轴研究计划
  • 批准号:
    8355145
  • 财政年份:
    2012
  • 资助金额:
    $ 62.79万
  • 项目类别:
Pulmonary Vascular-Right Ventricular Axis Research Program
肺血管-右心室轴研究计划
  • 批准号:
    8676934
  • 财政年份:
    2012
  • 资助金额:
    $ 62.79万
  • 项目类别:
Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*
气道氧化还原生物化学作为青春期哮喘表型的决定因素*
  • 批准号:
    8572752
  • 财政年份:
    2011
  • 资助金额:
    $ 62.79万
  • 项目类别:
Asthma Inflammation Research (AIR)
哮喘炎症研究 (AIR)
  • 批准号:
    8686052
  • 财政年份:
    2011
  • 资助金额:
    $ 62.79万
  • 项目类别:

相似海外基金

Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
  • 批准号:
    RGPIN-2021-04040
  • 财政年份:
    2022
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Discovery Grants Program - Individual
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
  • 批准号:
    547124-2020
  • 财政年份:
    2022
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
  • 批准号:
    547124-2020
  • 财政年份:
    2021
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Postgraduate Scholarships - Doctoral
Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
  • 批准号:
    RGPIN-2021-04040
  • 财政年份:
    2021
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Discovery Grants Program - Individual
The Molecular Mechanism of the Secretion of the Bacterial Toxin Adenylate Cyclase
细菌毒素腺苷酸环化酶分泌的分子机制
  • 批准号:
    451966
  • 财政年份:
    2021
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Operating Grants
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
  • 批准号:
    10455587
  • 财政年份:
    2020
  • 资助金额:
    $ 62.79万
  • 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
  • 批准号:
    10261394
  • 财政年份:
    2020
  • 资助金额:
    $ 62.79万
  • 项目类别:
Diagnosis and therapeutic effect of neurally mediated syncope (NMS) using fluctuation of adenylate cyclase activity
利用腺苷酸环化酶活性波动对神经介导性晕厥(NMS)的诊断和治疗效果
  • 批准号:
    20K08498
  • 财政年份:
    2020
  • 资助金额:
    $ 62.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Pituitary adenylate cyclase-activating polypeptide 27 in the paraventricular thalamus and its projections: Role in ethanol drinking
室旁丘脑中的垂体腺苷酸环化酶激活多肽 27 及其预测:在乙醇饮用中的作用
  • 批准号:
    10380126
  • 财政年份:
    2020
  • 资助金额:
    $ 62.79万
  • 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
  • 批准号:
    10662279
  • 财政年份:
    2020
  • 资助金额:
    $ 62.79万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了