Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension

激肽B1受体在高血压中的神经免疫机制

• 批准号: 10238100
• 负责人: Srinivas Sriramula
• 金额: $ 36.88万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238100
• 关键词: Address; Agonist; Angiotensins; Attenuated; Autonomic Dysfunction; Bradykinin; Brain; Brain region; Carboxypeptidase; Cardiovascular Diseases; Chronic; Cleaved cell; Data; Development; Disintegrins; Epidermal Growth Factor Receptor; Future; Genetic; Genetic Models; Heart failure; Human; Hypertension; In Vitro; Inflammation; Infusion procedures; Kidney Failure; Kinins; Knockout Mice; Link; Lysine Carboxypeptidase; Measures; Mediating; Medical; Metalloproteases; Methods; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Neuroimmune; Neuroimmunomodulation; Neurons; Organ; Oxidation-Reduction; Oxidative Stress; Patients; Peripheral; Pharmacology; Play; Prevalence; Production; Prognosis; Public Health; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Role; Signal Pathway; Signal Transduction; Spatial Distribution; Stroke; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Transactivation; United States; Up-Regulation; Vascular Diseases; Work; attenuation; base; blood pressure regulation; cardiovascular risk factor; cytokine; human subject; in vivo; insight; interdisciplinary approach; mitochondrial dysfunction; mortality; neurogenic hypertension; neuroinflammation; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; paraventricular nucleus; prevent; receptor; receptor expression; receptor upregulation; receptor-mediated signaling; salt sensitive hypertension

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.

项目总结/摘要 高血压（HTN）在美国仍然是一个重要的医疗和公共卫生问题。最新 治疗措施针对外周肾素-血管紧张素系统（RAS）。这些疗法已 降低高血压患者的发病率和死亡率。然而，患者的长期预后 高血压仍然很差，需要新的治疗方法。我们之前的研究表明， 脑ADAM 17（一种去整合素和金属蛋白酶）或血管紧张素II 1型受体（AT 1 R）的上调将 减少HTN的进展。我们最近的工作表明，激肽B1受体（B1 R）激活导致 下丘脑室旁核（PVN）等关键自主脑区炎症增加 并且B1 R的药理学阻断或基因缺失减弱神经源性HTN。另外我们 初步数据显示，B1 R表达在高血压人类受试者的PVN中升高。证据 提示升高的激肽酶I（羧肽酶，CPN/CPM，其将缓激肽切割成des-Arg 9- 缓激肽，B1 R的内源性激动剂）水平导致B1 R激动剂的内源性水平增加， 导致随后B1 R的上调和活化。刺激B1 R导致ADAM 17激活， 进而反式激活表皮生长因子受体（EGFR）。然而，确切的信号传导 在HTN中，B1 R和Kininase I的作用机制以及AT 1 R、ADAM 17和EGFR与B1 R的相互作用并不清楚。 清楚因此，在这项提议中，我们测试了中心假设，即大脑中B1 R信号的阻断 减少炎症和氧化应激，从而减少交感神经兴奋，导致衰减 神经源性高血压这一假设将通过以下具体目标进行检验：（1）确定是否针对 阻断B1 R信号传导可减弱神经源性HTN，（2）确定中枢B1 R激活的因果作用， 神经源性HTN的发生;（3）阐明HTN的信号转导机制和功能相互作用 神经源性HTN PVN中B1 R和AT 1 R/ADAM 17/EGFR之间的关系。在方法方面，我们将使用 最先进的体外和体内药理学和分子方法结合新颖独特的 遗传模型来研究HTN中B1 R的信号传导机制。该项目将确定新颖和重要的 B1 R信号传导在HTN中的作用，并为开发用于治疗人类HTN的新疗法提供见解。 神经源性高血压