Inflammatory Nicotinic Acetylcholine Receptors in a Genetic Model of Essential Hypertension

原发性高血压遗传模型中的炎症性烟碱乙酰胆碱受体

• 批准号: 10254791
• 负责人: Sailesh Harwani
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10254791
• 关键词: Acetylcholine; Adrenergic Agents; Adult; Affect; Agonist; Antihypertensive Agents; Autonomic nervous system; Basic Science; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular Structures; Chantix; Cholinergic Receptors; Clinical Sciences; Data; Denervation; Dependence; Development; Essential Hypertension; Evaluation; Event; Fill-It; Genetic; Genetic Models; Goals; Government; Health; Health system; Human; Hypertension; Immune; Immune response; Immune system; In Vitro; Inbred SHR Rats; Inflammation; Inflammatory; Knowledge; Maintenance; Mediating; Modeling; Molecular; Nerve; Nervous system structure; Neuroimmune; Neuroimmunomodulation; Neurons; Neurotransmitters; Nicotine; Nicotinic Receptors; Norepinephrine; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Prevalence; Process; Production; Receptor Activation; Resistance; Resistant Hypertension; Risk; Risk Factors; Role; Spleen; Testing; Therapeutic; Therapeutic Agents; Vascular System; Veterans; arm; cardiovascular risk factor; cholinergic; clinically significant; hemodynamics; human model; hypertensive; immune activation; in vivo; kidney medulla; kidney vascular structure; macrophage; military veteran; nerve supply; nicotine use; novel; novel therapeutics; paracrine; patient subsets; receptor; receptor binding; response; smoking cessation; varenicline

Nearly half of US adults have hypertension. Hypertension is also highly prevalent in the VA Health System. Traditionally, hypertension has been thought to be a function of abnormalities in the renal, vascular, and nervous systems. In recent years, clinical and basic science data clearly demonstrate that there is crosstalk between the nervous and immune systems, and the neuro-immune axis plays an integral part in development of hypertension. The neuro-immune axis describes a regulatory, bidirectional interaction between the autonomic nervous and immune systems. Activation of the nicotinic arm of this axis leads to both anti- and pro- inflammatory immune responses. We discovered that activation of the nicotinic acetylcholine receptor with nicotine (a non-selective agonist), both in vitro and in vivo, induces an inflammatory M1 macrophage population that infiltrates the renal medulla and leads to the development of hypertension in the genetic Spontaneously Hypertensive Rat (SHR) model of essential hypertension. Our long-term goal is to develop novel therapeutic agents to target this cholinergic arm of the neuro-immune axis in human essential hypertension. The short-term goal of this proposal is to identify the nicotinic acetylcholine receptors involved in this cholinergic arm, and to explore their role in the development of essential hypertension. The central hypothesis of this proposal is that a specific arm of the nicotinic acetylcholine receptor-mediated immune response favors inflammatory mechanisms to promote the development of hypertension. This hypothesis is grounded in novel and exciting preliminary data showing that the alpha4beta2 subtype of the nicotinic acetylcholine receptor is upregulated in immune cells in the SHR model of essential hypertension, and that selective activation of the alpha4beta2nicotinic acetylcholine receptor leads to the development of hypertension. Using state-of-the-art in vivo and in vitro molecular and cellular approaches, as well as in vivo hemodynamics, this proposal will 1) determine the role of the alpha4beta2 subtype of the nicotinic acetylcholine receptor in pro-inflammatory immune cells responses; 2) explore whether the alpha4beta2 nicotinic acetylcholine receptor plays a causal role in the development and maintenance of essential hypertension; and 3) examine whether splenic innervation promotes expansion of immune cells endowed with the alpha4beta2 nicotinic acetylcholine receptor, and thus an inflammatory phenotype, in essential hypertension. Essential hypertension is the most prevalent cardiovascular condition in the VA Health System and remains undertreated. Major gaps in our understanding of the neuro-immune axis limit our ability to treat hypertension. This application provides a unique opportunity to better understand this axis and may therefore open the door for new anti-hypertensive therapeutics.

近一半的美国成年人患有高血压。高血压在 VA Health 中也很普遍 系统。传统上，高血压被认为是肾功能异常的结果， 血管、神经系统。近年来的临床和基础科学数据清楚地表明： 神经系统和免疫系统之间存在串扰，神经免疫轴起着不可或缺的作用 参与高血压的发展。 神经免疫轴描述了自主神经之间的调节性、双向相互作用。 神经和免疫系统。该轴烟碱臂的激活会导致反烟碱和亲烟碱 炎症免疫反应。我们发现烟碱乙酰胆碱受体的激活 尼古丁（一种非选择性激动剂）在体外和体内均可诱导炎症性 M1 巨噬细胞 浸润肾髓质并导致遗传性高血压发生的人群 原发性高血压自发性高血压大鼠（SHR）模型。我们的长期目标是发展 针对人类必需神经免疫轴的胆碱能臂的新型治疗剂 高血压。该提案的短期目标是鉴定烟碱乙酰胆碱受体 参与这个胆碱能臂，并探索它们在基本发育中的作用 高血压。 该提议的中心假设是烟碱乙酰胆碱受体介导的特定臂 免疫反应有利于炎症机制，促进高血压的发展。这 该假设基于新颖且令人兴奋的初步数据，表明 alpha4beta2 亚型 在必需的 SHR 模型中，免疫细胞中烟碱乙酰胆碱受体的表达上调 高血压，α4β2烟碱乙酰胆碱受体的选择性激活导致 到高血压的发展。使用最先进的体内和体外分子和细胞 方法以及体内血流动力学，该提案将 1) 确定 促炎免疫细胞中烟碱乙酰胆碱受体的α4β2亚型 回应； 2）探索α4β2烟碱乙酰胆碱受体是否发挥因果作用 原发性高血压的发生和维持； 3) 检查脾脏是否 神经支配促进具有 α4β2 烟碱的免疫细胞的扩张 乙酰胆碱受体，从而导致原发性高血压的炎症表型。 原发性高血压是退伍军人管理局医疗系统中最常见的心血管疾病， 仍未得到充分治疗。我们对神经免疫轴理解的重大差距限制了我们的能力 来治疗高血压。该应用程序提供了一个更好地了解该轴的独特机会 因此可能为新的抗高血压疗法打开大门。