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.

近一半的美国成年人患有高血压。高血压在退伍军人健康中也非常普遍 系统。传统上，高血压被认为是肾脏异常的一种功能， 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，神经免疫轴起着不可或缺的作用。 参与高血压的发生发展。 神经免疫轴描述了自主神经之间的调节的双向相互作用。 神经和免疫系统。这一轴的烟碱臂的激活导致反和亲- 炎性免疫反应。我们发现，烟碱型乙酰胆碱受体的激活 尼古丁(一种非选择性激动剂)在体外和体内都能诱导炎性M1巨噬细胞 侵袭肾髓质并导致遗传性高血压的人群 自发性高血压大鼠(SHR)高血压模型。我们的长远目标是发展 以人类必需神经免疫轴的胆碱能臂为靶点的新型治疗药物 高血压。这项提议的短期目标是确定烟碱型乙酰胆碱受体 参与这一胆碱能臂，并探讨其在发育中的重要作用 高血压。 这一建议的中心假设是烟碱型乙酰胆碱受体的一条特定臂介导 免疫反应有利于炎症机制，促进高血压的发展。这 假说的基础是新的和令人兴奋的初步数据显示，alpha4beta2亚型 在SHR模型中，烟碱型乙酰胆碱受体在免疫细胞中表达上调 高血压和选择性激活α4β2烟碱型乙酰胆碱受体导联 与高血压的发展有关。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，这一建议将1)决定 促炎免疫细胞烟碱型乙酰胆碱受体的α4β2亚型 2)探讨α4beta2烟碱型乙酰胆碱受体是否起因果作用 在高血压病的发展和维持中；3)检查脾是否 神经支配促进携带α4β2烟碱的免疫细胞的扩张 乙酰胆碱受体，因此是一种炎症表型，在高血压。 高血压是退伍军人健康系统中最常见的心血管疾病， 仍然得不到足够的治疗。我们对神经免疫轴的理解上的重大差距限制了我们的能力 治疗高血压。这个应用程序为更好地理解这一轴提供了一个独特的机会 因此可能会为新的抗高血压疗法打开大门。