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: 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
• 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

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.

项目摘要/摘要 在美国，高血压（HTN）仍然是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）。这些疗法具有 高血压患者的发病率和死亡率降低。但是，患者的长期预后 高血压仍然很差，需要新的治疗方法。我们先前表明抑制 脑ADAM17（拆解蛋白和金属蛋白酶）或血管紧张素II 1型受体（AT1R）上调 减少HTN的进展。我们最近的工作表明Kinin B1受体（B1R）激活导致 关键自主脑区域的炎症升高，例如下丘脑室室核（PVN） B1R的药理阻滞或遗传缺失减弱了神经源HTN。另外，我们的 初步数据表明，在高血压人类受试者的PVN中，B1R表达升高。证据 表明升高的激酶I（羧肽酶，CPN/cpm，将心动激肽切割到DES-ARG9-- Bradyinin，B1R）水平的内源性激动剂是内源性b1r激动剂的增加， 导致随后的上调和激活B1R。刺激B1R导致ADAM17激活 反过来反复激活表皮生长因子受体（EGFR）。但是，确切的信号传输 B1R和激酶I的机制，以及AT1R，ADAM17和EGFR与B1R的相互作用，在HTN中不是 清除。因此，在此提案中，我们检验了中心假设，即B1R信号在大脑中的阻塞 减轻炎症和氧化应激，从而减少交感神经，导致衰减 神经源HTN。该假设将通过以下特定目的来检验：（1）确定是否针对 B1R信号的阻断减弱了神经源HTN，（2）确定中央B1R激活的因果作用 神经源HTN的发展，（3）阐明了信号传导机制和功能相互作用 在神经源HTN中的PVN中的B1R和AT1R/ADAM17/EGFR之间。在方法方面，我们将使用 最新的体外和体内药理和分子方法与新颖和独特的 研究HTN中B1R的信号传导机制的遗传模型。这个项目将确定小说和至关重要 B1R信号在HTN中的作用，并提供了开发新疗法治疗人类的见解 神经源HTN。