The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension.

脑细胞衰老在高血压性别二态性中的作用。

基本信息

  • 批准号:
    10656211
  • 负责人:
  • 金额:
    $ 4.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY It is estimated that about 10 million deaths worldwide each year are associated with hypertension, but unfortunately, the etiology is unknown in 95% of cases. Furthermore, the risk of hypertension is greater in men than pre-menopausal women. However, post-menopause, the female risk of hypertension exceeds that of age- matched males, pointing to the hormone estrogen as protective against hypertension. In contrast to the cardiovascular protective effects of estrogen, the hormone angiotensin II (Ang II) is well-recognized as a driver of hypertension. Ang II acts within the brain to elevate sympathetic nervous system outflow, which subsequently leads to increases in blood pressure. Indeed, hypertensive patients display elevated levels of Ang II and sympathetic overactivity. As a peptide hormone, Ang II is too large to cross the blood-brain-barrier and influences cardiovascular regulation at specialized circumventricular nuclei that lack a blood-brain-barrier, particularly the subfornical organ (SFO). Ang II-induced cellular stressors including oxidative stress and endoplasmic reticulum dysfunction within the SFO are strongly implicated in Ang II-induced hypertension. However, the integrative downstream cellular mechanisms by which these alterations in the SFO lead to chronic changes in neuronal function remains unclear. Interestingly, these stressors have been shown to induce cellular senescence - a complex cellular phenotype characterized by marked changes in cell metabolism, macromolecular damage, and a secretory pro-inflammatory environment known as the senescence associated secretory phenotype (SASP). Our key preliminary data in murine models reveals that central nervous system senescence contributes to hypertension. Additional exciting evidence indicates that Ang II drives senescence and SASP activation in the SFO of males, but not in females. Building upon this, the current proposal will test the hypothesis that estrogen is protective against SFO cellular senescence/SASP and subsequently hypertension development. To address this hypothesis, we will comprehensively characterize SFO cellular senescence/SASP in male versus female mice during Ang II-induced hypertension development using molecular, histological, and innovative in vivo imaging techniques. We will further determine the functional consequence of cellular senescence on SFO neurons and how the sexual dimorphism of hypertension is driven by the interplay between SFO Ang II-mediated senescence and estrogen. Findings from this proposal have the potential to advance our understanding of sexually dimorphic brain mechanisms in hypertension pathology, which may spur novel therapeutic treatments for hypertension in both sexes.
项目摘要 据估计,全球每年约有1000万例死亡与高血压有关, 不幸的是,95%的病例病因不明。此外,男性患高血压的风险更大 比绝经前的妇女更容易然而,绝经后,女性患高血压的风险超过了年龄- 配对的男性,指出雌激素对高血压有保护作用。相对于 心血管保护作用的雌激素,激素血管紧张素II(Ang II)是公认的驱动程序 高血压血管紧张素II在脑内起作用,以提高交感神经系统的流出, 导致血压升高。事实上,高血压患者显示升高的Ang II水平, 交感神经过度活跃作为一种肽类激素,血管紧张素II太大而不能穿过血脑屏障, 心血管调节在专门的室周核,缺乏血脑屏障,特别是 穹窿下器官(SFO)。血管紧张素II诱导的细胞应激因子,包括氧化应激和内质网 SFO内的功能障碍与Ang II诱导的高血压密切相关。然而,综合 SFO中的这些改变导致神经元慢性变化的下游细胞机制 功能尚不清楚。有趣的是,这些应激源已被证明会诱导细胞衰老-- 复杂的细胞表型,其特征在于细胞代谢、大分子损伤和 一种称为衰老相关分泌表型(SASP)的分泌促炎环境。 我们在小鼠模型中的关键初步数据表明,中枢神经系统衰老有助于 高血压其他令人兴奋的证据表明,血管紧张素II驱动衰老和SASP激活, 男性的SFO,但女性没有。在此基础上,目前的提议将测试雌激素 对SFO细胞衰老/SASP和随后的高血压发展具有保护作用。解决 根据这一假设,我们将全面描述男性与女性的SFO细胞衰老/SASP, 在血管紧张素II诱导的高血压发展过程中,使用分子,组织学和创新的体内 成像技术。我们将进一步确定细胞衰老对SFO的功能影响 神经元以及高血压的性二态性是如何由SFO Ang II介导的 衰老和雌激素这项提案的结果有可能促进我们对以下问题的理解: 高血压病理学中的性二态脑机制,这可能会刺激新的治疗方法 对高血压的影响

项目成果

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Samantha Annie Dow其他文献

Samantha Annie Dow的其他文献

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{{ truncateString('Samantha Annie Dow', 18)}}的其他基金

The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension.
脑细胞衰老在高血压性别二态性中的作用。
  • 批准号:
    10464412
  • 财政年份:
    2022
  • 资助金额:
    $ 4.07万
  • 项目类别:

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