Role of HIF1-alpha and Renal afferents in Activation of the PVN in Heart Failure

HIF1-α 和肾传入在心力衰竭中 PVN 激活中的作用

基本信息

  • 批准号:
    8903575
  • 负责人:
  • 金额:
    $ 35.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of morbidity and mortality. Standard therapy is to attempt to contain this sympatho- excitation in the face of reduced cardiac output. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to this elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanism mediated by 1) an intra-PVN hypoxia-inducible factor (HIF-1�) mechanism: We have found that HIF-1� protein is increased in the PVN of rats with HF; A HIF-1� siRNA administered to the PVN normalizes the increased renal sympathetic nerve activity in rats with HF. 2) A renal nerve dependent mechanism: Renal denervation (RDN) is a new effective therapy for reducing sympathetic outflow in patients with hypertension. Our preliminary data shows that RDN reduces norepinephrine excretion in rats with HF, but not in sham rats, suggesting that RDN reduces sympatho-excitation in HF. Finally, as a therapeutic modality we have shown that exercise training (ExT) reduces activation of HIF-1� in the PVN and decreases neuro- humoral activation in HF. This proposal tests the hypothesis that activation of HIF-1� and/or ascending information from the renal nerves contributes to the increased sympathetic drive in HF. Furthermore, ExT, may normalizes levels of HIF-1� and/or renal afferent input to the PVN in HF. We propose to determine the underlying mechanisms for the activation of HIF-1� and/or ascending information from the renal nerves at the level of the PVN and subsequent sympatho-excitation in rats with HF. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact whole animals to studies in brain nuclei to individual neurons. We will use a variety of complementary techniques involving electrophysiological, neuroanatomical, immunohistochemical, molecular, cellular, and lentiviral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of HIF-1� and/or ascending information from the renal nerves to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.
描述(由申请人提供):心力衰竭(HF)患者和所有HF动物模型均表现出交感神经激活增加,这增加了发病率和死亡率的风险。标准的治疗方法是在心输出量减少的情况下试图抑制这种交感神经兴奋。我们先前已经观察到,下丘脑室旁核(PVN)内的神经元激活可能有助于这种升高的神经体液驱动。这种激活的机制和来源仍有待明确界定。最近,我们发现了由1)室旁核内缺氧诱导因子(HIF-1 β)机制介导的增强兴奋机制:我们发现HF大鼠室旁核中HIF-1 β蛋白增加;给予室旁核HIF-1 β siRNA使HF大鼠肾交感神经活动正常化。2)肾神经依赖性机制:去肾神经支配(RDN)是减少高血压患者交感神经流出的一种新的有效治疗方法。我们的初步数据表明,RDN减少HF大鼠的去甲肾上腺素排泄,但在假手术大鼠中没有,这表明RDN减少HF的交感兴奋。最后,作为一种治疗方式,我们已经表明,运动训练(ExT)减少了PVN中HIF-1 β的激活,并减少了HF中的神经体液激活。这项提议验证了HIF-1 β和/或来自肾神经的上行信息的激活有助于HF中交感神经驱动增加的假设。此外,ExT可以使HF中的HIF-1 β和/或肾传入输入到PVN的水平正常化。我们建议确定HF大鼠PVN水平上HIF-1 β激活和/或肾神经上行信息以及随后的交感兴奋的潜在机制。这一目标将通过利用多学科的方法来实现,从完整的整个动物的研究到脑细胞核的研究到单个神经元的研究。我们将使用各种互补技术,包括电生理学、神经解剖学、免疫组织化学、分子、细胞和慢病毒基因转移技术。这些结果将提供关于交感神经兴奋的中枢机制的重要新信息,特别是HIF-1 β和/或从肾神经到PVN的上行信息在HF状态下增加交感神经激活中的参与。了解这些中枢机制在交感神经驱动增加中的作用,将提高我们治疗HF及其心血管并发症的能力。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Exercise Training Attenuates Upregulation of p47(phox) and p67(phox) in Hearts of Diabetic Rats.
Role of Chemoreceptor Activation in Hemodynamic Responses to Electrical Stimulation of the Carotid Sinus in Conscious Rats.
  • DOI:
    10.1161/hypertensionaha.115.05316
  • 发表时间:
    2015-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Katayama PL;Castania JA;Dias DP;Patel KP;Fazan R Jr;Salgado HC
  • 通讯作者:
    Salgado HC
{{ 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 }}

KAUSHIK P PATEL其他文献

KAUSHIK P PATEL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('KAUSHIK P PATEL', 18)}}的其他基金

Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure
SGLT2 抑制对充血性心力衰竭有益作用的新靶点机制(肾神经)
  • 批准号:
    10669642
  • 财政年份:
    2021
  • 资助金额:
    $ 35.42万
  • 项目类别:
Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure
SGLT2 抑制对充血性心力衰竭有益作用的新靶点机制(肾神经)
  • 批准号:
    10472675
  • 财政年份:
    2021
  • 资助金额:
    $ 35.42万
  • 项目类别:
Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure
SGLT2 抑制对充血性心力衰竭有益作用的新靶点机制(肾神经)
  • 批准号:
    10275320
  • 财政年份:
    2021
  • 资助金额:
    $ 35.42万
  • 项目类别:
Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure
减少慢性心力衰竭钠潴留的新靶点机制(去肾神经)
  • 批准号:
    9365386
  • 财政年份:
    2017
  • 资助金额:
    $ 35.42万
  • 项目类别:
Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure
减少慢性心力衰竭钠潴留的新靶点机制(去肾神经)
  • 批准号:
    9925231
  • 财政年份:
    2017
  • 资助金额:
    $ 35.42万
  • 项目类别:
Exercise training improves erectile dysfunction in diabetes: role of central mech
运动训练可改善糖尿病患者的勃起功能障碍:中枢机械的作用
  • 批准号:
    8242632
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:
Exercise training improves erectile dysfunction in diabetes: role of central mech
运动训练可改善糖尿病患者的勃起功能障碍:中枢机械的作用
  • 批准号:
    7572274
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:
Exercise training improves erectile dysfunction in diabetes: role of central mech
运动训练可改善糖尿病患者的勃起功能障碍:中枢机械的作用
  • 批准号:
    7789650
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:
The Role of Excitatory Input into the PVN on Increased Sympathetic Drive in Heart
PVN 兴奋性输入对心脏交感神经驱动增强的作用
  • 批准号:
    7750833
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:
Exercise training improves erectile dysfunction in diabetes: role of central mech
运动训练可改善糖尿病患者的勃起功能障碍:中枢机械的作用
  • 批准号:
    8039089
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了