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: 10512748
• 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/10512748
• 关键词: Acetylcholine; Adrenergic Agents; Adult; Affect; Agonist; Antihypertensive Agents; Autonomic nervous system; Basic Science; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cells; Chantix; Cholinergic Receptors; Clinical Sciences; Data; Denervation; Dependence; Development; Endowment; Essential Hypertension; Evaluation; Event; Genetic; Genetic Models; Goals; Government; Health; Health system; Human; Hypertension; Immune; Immune response; Immune system; In Vitro; Inbred SHR Rats; Infiltration; Inflammation; Inflammatory; Kidney; Knowledge; Macrophage; Maintenance; Mediating; Modeling; Molecular; Nerve; Nervous System; 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; 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.

我们近一半的成年人患有高血压。高血压在VA健康中也很普遍 系统。传统上，高血压被认为是肾脏异常的功能， 血管和神经系统。近年来，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，而神经免疫轴则具有积分 高血压发展的一部分。 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。该轴的烟碱臂的激活导致抗抗和前 炎症免疫反应。我们发现烟碱乙酰胆碱受体激活 尼古丁（一种非选择性激动剂）在体外和体内都会诱发炎症性M1巨噬细胞 浸润肾脏髓质并导致高血压发展的种群 基本高血压的自发高血压大鼠（SHR）模型。我们的长期目标是发展 靶向人类必需神经免疫轴这一胆碱能臂的新型治疗剂 高血压。该建议的短期目标是识别烟碱乙酰胆碱受体 参与这个胆碱能的部门，并探索它们在基本发展中的作用 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 假设基于新颖而令人兴奋的初步数据，表明alpha4beta2亚型 烟碱乙酰胆碱受体在免疫细胞中的SHR模型中上调 高血压，并选择性激活α4beta2nicotinic乙酰胆碱受体铅 高血压的发展。使用最新的体内和体外分子和细胞 方法以及体内血流动力学，该建议将确定 促炎性免疫细胞中烟碱乙酰胆碱受体的α4BETA2亚型 回应； 2）探索α4Beta2烟碱乙酰胆碱受体是否起因果作用 在基本高血压的发展和维持中； 3）检查是否脾脏 神经神经促进具有alpha4beta2烟碱的免疫细胞的扩张 乙酰胆碱受体，因此是必需高血压的炎症表型。 基本高血压是VA卫生系统中最普遍的心血管疾病 保持不足。我们对神经免疫轴的理解的主要差距限制了我们的能力 治疗高血压。该应用程序提供了一个独特的机会来更好地了解此轴 因此，可以为新的抗高血压治疗剂打开大门。