Angiotensin-(1-7) and Hypothalamic control of blood pressure

血管紧张素-(1-7) 和下丘脑对血压的控制

基本信息

项目摘要

PROJECT SUMMARY Obesity is a global epidemic that is associated with excessive central sympathetic outflow to cardiovascular end organs to elevate blood pressure and predispose to hypertension. Accumulating evidence from our laboratory suggests that deficiency of angiotensin-(1-7), a protective hormone of the renin-angiotensin system, provides an important link connecting obesity with sympathetic overactivation and hypertension. Our published observations, combined with preliminary data, support this concept by showing that high fat diet-induced obese mice exhibit circulating angiotensin-(1-7) deficiency, and restoration of this hormone attenuates cardiovascular sympathetic overactivity and hypertension in this model. Our preliminary data expand on these phenotypic findings by providing evidence that angiotensin-(1-7) depressor effects require activation of neural circuits originating in the arcuate nucleus of the hypothalamus (ARC). We show that both systemic and intra-ARC angiotensin-(1-7) lowers blood pressure in mice, with effects prevented by deletion of angiotensin-(1-7) mas receptors in the ARC. We further show that blood pressure lowering effects of angiotensin-(1-7) require activation of specific subpopulations of ARC neurons that are likely proopiomelanocortin (POMC)-expressing, as well as cyclic AMP second messenger systems. We propose that angiotensin-(1-7) selectively activates POMC neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In support of this, we show that: mas receptors are highly localized to GABAergic POMC neurons; and angiotensin-(1-7) increases GABA synthesis enzymes in the ARC without altering POMC gene expression. Based on these data, this proposal will test the central hypothesis that angiotensin-(1-7) activates mas receptors on GABAergic POMC neurons in the ARC to reduce cardiovascular sympathetic outflow and lower blood pressure. Aim 1 will determine if angiotensin-(1-7) selectively increases the excitability of GABAergic ARC POMC neurons using transgenic mouse reporter lines combined with whole cell patch clamp electrophysiology methods. Aim 2 will determine if angiotensin-(1-7) requires mas receptors in ARC POMC neurons to lower blood pressure via GABA release mechanisms using a novel mas receptor conditional knockout mouse model we developed and chemogenetic and pharmacological approaches. Aim 3 will determine if angiotensin-(1-7) decreases sympathetic nerve traffic to cardiovascular organs using sophisticated in vivo isolated nerve recording approaches. These studies will be conducted in male and female mice under control and high fat diet conditions, to determine the impact of sex and obesity on angiotensin-(1-7) activation of this neural circuit. Overall, this proposal will span the cellular to whole animal levels to provide new insight into angiotensin-(1-7) effects on neural circuits controlling sympathetic outflow and blood pressure, and related cellular and neurotransmitter mechanisms. Importantly, these studies have more long-term potential to determine if targeting angiotensin-(1-7) represents a novel approach for the treatment of obesity-related hypertension.
项目概要 肥胖是一种全球流行病,与中枢交感神经过度流向心血管有关 终末器官会导致血压升高并诱发高血压。从我们收集的证据 实验室表明缺乏血管紧张素-(1-7),肾素-血管紧张素系统的保护性激素, 提供了肥胖与交感神经过度激活和高血压之间的重要联系。我们发表的 观察结果与初步数据相结合,表明高脂肪饮食引起的肥胖支持了这一概念。 小鼠表现出循环血管紧张素(1-7)缺乏,这种激素的恢复会减弱心血管 该模型中存在交感神经过度活跃和高血压。我们的初步数据扩展了这些表型 通过提供血管紧张素(1-7)抑制作用需要激活神经回路的证据来发现 起源于下丘脑弓状核(ARC)。我们表明,系统性和 ARC 内 血管紧张素-(1-7) 可降低小鼠血压,但通过删除血管紧张素-(1-7) mas 可以阻止其作用 ARC 中的受体。我们进一步表明,血管紧张素-(1-7) 的降血压作用需要 激活可能表达阿黑皮素原 (POMC) 的 ARC 神经元特定亚群, 以及环状 AMP 第二信使系统。我们认为血管紧张素-(1-7) 选择性激活 POMC 神经元释放抑制性神经递质 γ-氨基丁酸 (GABA)。支持 对此,我们表明: mas 受体高度定位于 GABA 能 POMC 神经元;和血管紧张素-(1-7) 增加 ARC 中的 GABA 合成酶,而不改变 POMC 基因表达。根据这些数据, 该提案将测试血管紧张素-(1-7) 激活 GABA 能上的 mas 受体的中心假设 ARC中的POMC神经元减少心血管交感神经流出并降低血压。目标1将 确定血管紧张素-(1-7)是否选择性地增加 GABAergic ARC POMC 神经元的兴奋性 转基因小鼠报告系与全细胞膜片钳电生理学方法相结合。目标2将 确定血管紧张素-(1-7)是否需要 ARC POMC 神经元中的 mas 受体来降低血压 使用我们开发的新型 mas 受体条件敲除小鼠模型的 GABA 释放机制 化学遗传学和药理学方法。目标 3 将确定血管紧张素-(1-7) 是否减少 使用复杂的体内隔离神经记录将交感神经传输至心血管器官 接近。这些研究将在受控制且高脂肪饮食的雄性和雌性小鼠中进行 条件,以确定性别和肥胖对该神经回路的血管紧张素(1-7)激活的影响。 总体而言,该提案将跨越细胞到整个动物水平,为血管紧张素-(1-7)提供新的见解 对控制交感神经流出和血压的神经回路以及相关细胞和 神经递质机制。重要的是,这些研究具有更长期的潜力来确定是否 靶向血管紧张素-(1-7)代表了治疗肥胖相关高血压的一种新方法。

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 }}

Amy Christine Arnold其他文献

Amy Christine Arnold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('Amy Christine Arnold', 18)}}的其他基金

Angiotensin-(1-7) and Hypothalamic control of blood pressure
血管紧张素-(1-7) 和下丘脑对血压的控制
  • 批准号:
    10178215
  • 财政年份:
    2021
  • 资助金额:
    $ 44.99万
  • 项目类别:
Angiotensin-(1-7) and Hypothalamic control of blood pressure
血管紧张素-(1-7) 和下丘脑对血压的控制
  • 批准号:
    10381736
  • 财政年份:
    2021
  • 资助金额:
    $ 44.99万
  • 项目类别:
Autonomic: Angiotensin-(1-7) Interactions in Hypertension
自主神经:高血压中血管紧张素 (1-7) 的相互作用
  • 批准号:
    8821988
  • 财政年份:
    2014
  • 资助金额:
    $ 44.99万
  • 项目类别:

相似海外基金

The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
  • 批准号:
    EP/Z000920/1
  • 财政年份:
    2025
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
  • 批准号:
    FT230100276
  • 财政年份:
    2024
  • 资助金额:
    $ 44.99万
  • 项目类别:
    ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
  • 批准号:
    MR/X024261/1
  • 财政年份:
    2024
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
  • 批准号:
    DE240100388
  • 财政年份:
    2024
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
  • 批准号:
    2232190
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Continuing Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
  • 批准号:
    2337595
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
  • 批准号:
    23K17514
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Analysis of thermoregulatory mechanisms by the CNS using model animals of female-dominant infectious hypothermia
使用雌性传染性低体温模型动物分析中枢神经系统的体温调节机制
  • 批准号:
    23KK0126
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Fund for the Promotion of Joint International Research (International Collaborative Research)
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
  • 批准号:
    2842926
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
  • 批准号:
    NC/X001644/1
  • 财政年份:
    2023
  • 资助金额:
    $ 44.99万
  • 项目类别:
    Training Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了