Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension

项目摘要/摘要 高血压(HTN)在美国仍然是一个重要的医学和公共卫生问题。最新版本 治疗措施针对外周肾素-血管紧张素系统(RAS)。这些疗法有 降低高血压患者的发病率和死亡率。然而，慢性阻塞性肺疾病患者的长期预后 高血压仍然很差，需要新的治疗方法。我们之前已经证明，抑制 大脑ADAM17(A去整合素和金属蛋白酶)或血管紧张素II 1型受体(AT1R)将上调 延缓HTN的进展。我们最近的工作表明，激动素B1受体(B1R)的激活导致 下丘脑室旁核(PVN)等关键自主神经脑区炎症升高 药物阻断或B1R基因缺失可减轻神经源性HTN。此外，我们的 初步数据显示，B1R在高血压病患者的PVN中表达升高。证据 提示激氨酸酶I(Cpn/Cpm)升高，可将缓激肽裂解成Des-Arg9- 缓激肽，一种B1R的内源性激动剂，解释了B1R激动剂内源性水平的增加， 从而导致B1R的随后上调和激活。刺激B1R导致ADAM17激活， 进而反式激活表皮生长因子受体(EGFR)。然而，确切的信号转导 在HTN中，B1R和Kininase I的作用机制以及AT1R、ADAM17和EGFR与B1R的相互作用未见报道 安全。因此，在这项提议中，我们检验了中心假设，即大脑中B1R信号的阻断 减少炎症和氧化应激，从而减少交感神经兴奋，导致减弱 神经源性HTN。这一假设将通过以下具体目标进行检验：(1)确定是否有针对性 阻断B1R信号减弱神经源性HTN，(2)确定中枢B1R激活在 神经源性HTN的发展；(3)阐明HTN的信号机制和功能相互作用 神经源性HTN室旁核B1R与AT1R/ADAM17/EGFR之间的关系在方法方面，我们将使用 最新体内外药理和分子方法结合新颖独特 研究HTN中B1R信号传导机制的遗传模型。该项目将确定新的和重要的 B1R信号在HTN中的作用并为开发治疗人类HTN的新疗法提供启示 神经源性HTN。

Project Summary/Abstract Hypertension (HTN) remains an important medical and public health issue in the United States. Most current therapeutic measures are targeted against the peripheral renin-angiotensin system (RAS). These therapies have reduced the morbidity and mortality in hypertensive patients. However, the long-term prognosis in patients with hypertension remains poor, and new therapeutic approaches are needed. We previously showed that inhibiting brain ADAM17 (A Disintegrin and Metalloprotease) or angiotensin II type 1 receptor (AT1R) upregulation will reduce the progression of HTN. Our recent work indicates that kinin B1 receptor (B1R) activation leads to elevated inflammation in key autonomic brain regions such as the hypothalamic paraventricular nucleus (PVN) and pharmacological blockade or genetic deletion of B1R attenuates neurogenic HTN. In addition, our preliminary data shows that B1R expression is elevated in the PVN of hypertensive human subjects. Evidence suggests that elevated kininase I (carboxypeptidase, CPN/CPM that cleaves bradykinin into des-Arg9- bradykinin, an endogenous agonist for B1R) levels account for increasing endogenous levels of B1R agonists, leading to subsequent upregulation and activation of B1R. Stimulation of B1R results in ADAM17 activation that in turn transactivates epidermal growth factor receptor (EGFR). However, the exact signal transduction mechanisms of B1R and Kininase I, and interactions of AT1R, ADAM17 and EGFR with B1R, in HTN are not clear. Therefore, in this proposal, we test the central hypothesis that the blockade of B1R signaling in the brain reduces inflammation and oxidative stress, thereby decreasing sympathoexcitation, leading to attenuation of neurogenic HTN. This hypothesis will be tested by following specific aims: (1) Determine whether targeted blockade of B1R signaling attenuates neurogenic HTN, (2) Identify the causal role of central B1R activation to the development of neurogenic HTN, and (3) Elucidate the signaling mechanisms and functional interactions between B1R and AT1R/ADAM17/EGFR in the PVN in neurogenic HTN. In terms of approaches, we will use state-of-the-art in vitro and in vivo pharmacological and molecular methods combined with novel and unique genetic models to investigate the signaling mechanisms of B1R in HTN. This project will identify novel and vital role of B1R signaling in HTN and provide insights for developing new therapeutics for the treatment of human neurogenic HTN.