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

基本信息

批准号：
10028541
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
项目类别：
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/10028541
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 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 outcome forecast paraventricular nucleus prevent receptor receptor expression receptor upregulation receptor-mediated signaling salt sensitive hypertension

项目摘要

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.

项目概要/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）。这些疗法有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严重，需要新的治疗方法。我们之前表明，抑制大脑 ADAM17（一种解整合素和金属蛋白酶）或血管紧张素 II 1 型受体 (AT1R) 上调将减少 HTN 的进展。我们最近的工作表明激肽 B1 受体 (B1R) 激活会导致下丘脑室旁核 (PVN) 等关键自主脑区域炎症加剧药物阻断或 B1R 基因缺失可减轻神经源性 HTN。此外，我们的初步数据显示，高血压人类受试者的 PVN 中 B1R 表达升高。证据表明激肽酶 I（羧肽酶、CPN/CPM）升高，可将缓激肽裂解为 des-Arg9- 缓激肽（B1R 的内源性激动剂）水平导致 B1R 激动剂内源性水平增加，导致 B1R 随后上调和激活。刺激 B1R 会导致 ADAM17 激活，反过来反式激活表皮生长因子受体（EGFR）。然而，确切的信号转导 B1R 和激肽酶 I 的机制，以及 AT1R、ADAM17 和 EGFR 与 B1R 的相互作用，在 HTN 中的作用尚不明确。清除。因此，在这个提案中，我们测试了中心假设，即大脑中 B1R 信号传导的阻断减少炎症和氧化应激，从而减少交感神经兴奋，从而减弱神经源性高血压。该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 信号传导可减弱神经源性 HTN，(2) 确定中枢 B1R 激活的因果作用神经源性 HTN 的发展，以及 (3) 阐明信号传导机制和功能相互作用神经源性 HTN 中 PVN 中的 B1R 和 AT1R/ADAM17/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与新颖独特的相结合遗传模型研究 HTN 中 B1R 的信号传导机制。该项目将确定新颖且重要的 B1R 信号在 HTN 中的作用，并为开发治疗人类的新疗法提供见解神经源性高血压。