Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling

通过 G 偶联蛋白受体信号传导恢复心肌愈合

基本信息

  • 批准号:
    9324068
  • 负责人:
  • 金额:
    $ 28.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

Cardiac progenitor cells (CPCs) express an impressive complement of G-protein coupled receptors (GPCRs) distinct from those found on adult cardiomyocytes. This proposal tests the hypothesis that the expression of GPCRs and availability of their ligands at sites of injury can either enable or impair the proliferation, survival and differentiation of endogenous CPCs. We propose three aims in which we use CPCs isolated from WT and genetically engineered mouse hearts to examine GPCR regulated pathways that contribute to these responses and extend our findings to an in vivo myocardial infarct model. In Aim # 1 we use mRNA arrays, qPCR and protein expression assays to define resident GPCRs on cultured CPCs and determine if they are dynamically regulated by ischemic stress, ER stress, or differentiation. Further studies define the GPCRs that are most efficacious for eliciting CPC proliferation, survival, migration and differentiation and the specific G-proteins and effectors they utilize. In Aim #2 we test the hypothesis that RhoA signaling, and its regulation by SIP and other GPCRs can enhance the reparative properties of CPCs. Proposed studies use CPCs from genetically engineered RhoA and SIP receptor knockout mice to determine the SIP receptor subtypes and requirement for RhoA signaling in agonist stimulated CPC responses. The role of RhoA in activating and utilizing the downstream transcriptional co-activators MRTF-A and YAP is also examined. In vivo studies in SIP receptor and RhoA KO mice examine the regenerative capacity of resident CPCs following myocardial infarction (Ml). Aim #3 tests the hypothesis that changes in the complement of adrenergic (AdR) and Angll receptor (ATR) subtypes alter the proliferation and survival of CPCs and can induce mitochondrial damage and cell death through oxidative stress.We compare CPCs in which the complement of Pi vs. P2 and ATi vs. AT2 subtypes are altered and examine effects of ATR blockers and p-AdR blockers on proliferation and survival of CPCs. A final focus is on the possible salutary role of apAdR on CPCs in responses to sympathetic adrenergic stimulation and Ml. Our overall objective is to demonstrate that specific GPCRs and their signaling pathways can be used to maintain and enhance CPC function, with the long term goal of using these highly accessible drug targets as sites of intervention to promote myocardial healing. RELEVANCE (See instructions): Cardiomyocytes in the heart die when deprived of oxygen and as a consequence the heart becomes weak. Stem cells in the heart, if appropriately stimulated, could form new cardiomyocytes and prevent heart failure. We believe that specific G-protein coupled receptors on these cardiac progenitor cells may enhance this process and that drugs that regulate these receptors could be developed to heal the heart.
Cardiac progenitor cells (CPCs) express an impressive complement of G-protein coupled receptors (GPCRs) distinct from those found on adult cardiomyocytes. This proposal tests the hypothesis that the expression of GPCRs and availability of their ligands at sites of injury can either enable or impair the proliferation, survival and differentiation of endogenous CPCs. We propose three aims in which we use CPCs isolated from WT and genetically engineered mouse hearts to examine GPCR regulated pathways that contribute to these responses and extend our findings to an in vivo myocardial infarct model. In Aim # 1 we use mRNA arrays, qPCR and protein expression assays to define resident GPCRs on cultured CPCs and determine if they are dynamically regulated by ischemic stress, ER stress, or differentiation. Further studies define the GPCRs that are most efficacious for eliciting CPC proliferation, survival, migration and differentiation and the specific G-proteins and effectors they utilize. In Aim #2 we test the hypothesis that RhoA signaling, and its regulation by SIP and other GPCRs can enhance the reparative properties of CPCs. Proposed studies use CPCs from genetically engineered RhoA and SIP receptor knockout mice to determine the SIP receptor subtypes and requirement for RhoA signaling in agonist stimulated CPC responses. The role of RhoA in activating and utilizing the downstream transcriptional co-activators MRTF-A and YAP is also examined. In vivo studies in SIP receptor and RhoA KO mice examine the regenerative capacity of resident CPCs following myocardial infarction (Ml). Aim #3 tests the hypothesis that changes in the complement of adrenergic (AdR) and Angll receptor (ATR) subtypes alter the proliferation and survival of CPCs and can induce mitochondrial damage and cell death through oxidative stress.We compare CPCs in which the complement of Pi vs. P2 and ATi vs. AT2 subtypes are altered and examine effects of ATR blockers and p-AdR blockers on proliferation and survival of CPCs. A final focus is on the possible salutary role of apAdR on CPCs in responses to sympathetic adrenergic stimulation and Ml. Our overall objective is to demonstrate that specific GPCRs and their signaling pathways can be used to maintain and enhance CPC function, with the long term goal of using these highly accessible drug targets as sites of intervention to promote myocardial healing. RELEVANCE (See instructions): Cardiomyocytes in the heart die when deprived of oxygen and as a consequence the heart becomes weak. Stem cells in the heart, if appropriately stimulated, could form new cardiomyocytes and prevent heart failure. We believe that specific G-protein coupled receptors on these cardiac progenitor cells may enhance this process and that drugs that regulate these receptors could be developed to heal the heart.

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 }}

JOAN HELLER BROWN其他文献

JOAN HELLER BROWN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('JOAN HELLER BROWN', 18)}}的其他基金

Cardiomyocyte CaM kinase II as a driver of cardiac inflammation and remodeling
心肌细胞 CaM 激酶 II 作为心脏炎症和重塑的驱动因素
  • 批准号:
    10308392
  • 财政年份:
    2018
  • 资助金额:
    $ 28.45万
  • 项目类别:
RhoA and GPCR mediated transcriptional activation regulates glioblastoma
RhoA 和 GPCR 介导的转录激活调节胶质母细胞瘤
  • 批准号:
    9905280
  • 财政年份:
    2018
  • 资助金额:
    $ 28.45万
  • 项目类别:
RhoA and GPCR mediated transcriptional activation regulates glioblastoma
RhoA 和 GPCR 介导的转录激活调节胶质母细胞瘤
  • 批准号:
    10356023
  • 财政年份:
    2018
  • 资助金额:
    $ 28.45万
  • 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
  • 批准号:
    10341047
  • 财政年份:
    2017
  • 资助金额:
    $ 28.45万
  • 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
  • 批准号:
    10018829
  • 财政年份:
    2017
  • 资助金额:
    $ 28.45万
  • 项目类别:
ISHR 2013 World Congress
ISHR 2013 世界大会
  • 批准号:
    8597882
  • 财政年份:
    2013
  • 资助金额:
    $ 28.45万
  • 项目类别:
2010 Cardiac Regulatory Mechanisms Gordon Research Conference
2010年心脏调节机制戈登研究会议
  • 批准号:
    7905509
  • 财政年份:
    2010
  • 资助金额:
    $ 28.45万
  • 项目类别:
Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling
通过 G 偶联蛋白受体信号转导恢复心肌愈合
  • 批准号:
    8452816
  • 财政年份:
    2006
  • 资助金额:
    $ 28.45万
  • 项目类别:
Cell Biology and Histology
细胞生物学和组织学
  • 批准号:
    8734480
  • 财政年份:
    2006
  • 资助金额:
    $ 28.45万
  • 项目类别:
Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling
通过 G 偶联蛋白受体信号转导恢复心肌愈合
  • 批准号:
    8734475
  • 财政年份:
    2006
  • 资助金额:
    $ 28.45万
  • 项目类别:

相似海外基金

Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
  • 批准号:
    8358448
  • 财政年份:
    2012
  • 资助金额:
    $ 28.45万
  • 项目类别:
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
  • 批准号:
    8517552
  • 财政年份:
    2012
  • 资助金额:
    $ 28.45万
  • 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
  • 批准号:
    7952159
  • 财政年份:
    2009
  • 资助金额:
    $ 28.45万
  • 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
  • 批准号:
    7952152
  • 财政年份:
    2009
  • 资助金额:
    $ 28.45万
  • 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
  • 批准号:
    7719194
  • 财政年份:
    2008
  • 资助金额:
    $ 28.45万
  • 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
  • 批准号:
    7605416
  • 财政年份:
    2007
  • 资助金额:
    $ 28.45万
  • 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
  • 批准号:
    7605425
  • 财政年份:
    2007
  • 资助金额:
    $ 28.45万
  • 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
  • 批准号:
    7378753
  • 财政年份:
    2006
  • 资助金额:
    $ 28.45万
  • 项目类别:
Adrenergic Agents for Methamphetamine: Outpatient Trials
甲基苯丙胺肾上腺素药物:门诊试验
  • 批准号:
    6825160
  • 财政年份:
    2004
  • 资助金额:
    $ 28.45万
  • 项目类别:
ADRENERGIC AGENTS FOR CARDIOPULMONARY RESUSCITATION
用于心肺复苏的肾上腺素能药物
  • 批准号:
    2702283
  • 财政年份:
    1997
  • 资助金额:
    $ 28.45万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了