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

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(Pulmonary Arterial Hypertension, PAH)以肺动脉压升高为特征

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 }}

MARK W GERACI其他文献

MARK W GERACI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('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:
Lung Genomics Research Consortium
肺基因组学研究联盟
  • 批准号:
    7939886
  • 财政年份:
    2009
  • 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:
Lung Genomics Research Consortium
肺基因组学研究联盟
  • 批准号:
    8305295
  • 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:
Lung Genomics Research Consortium
肺基因组学研究联盟
  • 批准号:
    7853298
  • 财政年份:
    2009
  • 资助金额:
    $ 22.57万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 22.57万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了