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VA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，神经免疫轴在其中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和免疫系统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-和促- 炎症免疫反应。我们发现，激活烟碱乙酰胆碱受体， 尼古丁（一种非选择性激动剂）在体外和体内均诱导炎症性M1巨噬细胞 人群浸润肾髓质，并导致高血压的发展，在遗传 自发性高血压大鼠（SHR）原发性高血压模型。我们的长期目标是发展 靶向人原发性肝癌中神经免疫轴的胆碱能臂的新治疗剂 高血压这项建议的短期目标是确定烟碱乙酰胆碱受体 参与这一胆碱能臂，并探讨其在发展中的重要作用， 高血压 这一建议的中心假设是，烟碱乙酰胆碱受体介导的一个特定的手臂， 免疫反应有利于炎症机制，以促进高血压的发展。这 这一假说基于新的和令人兴奋的初步数据，这些数据表明α 4 β 2亚型 在自发性高血压大鼠模型中， 高血压和α 4 β 2烟碱乙酰胆碱受体选择性激活导致 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，以及在体内血液动力学，该建议将1）确定的作用， 促炎免疫细胞中烟碱乙酰胆碱受体的α 4 β 2亚型 反应; 2）探索α 4 β 2烟碱乙酰胆碱受体是否起因果作用 在原发性高血压的发展和维持;和3）检查是否脾 神经支配促进具有α 4 β 2烟碱受体的免疫细胞的扩增 乙酰胆碱受体，从而在原发性高血压炎症表型。 原发性高血压是VA卫生系统中最常见的心血管疾病， 仍然没有得到充分的治疗。我们对神经免疫轴的理解的主要差距限制了我们的能力 来治疗高血压这个应用程序提供了一个独特的机会，以更好地了解这个轴 因此可能为新的抗高血压治疗打开大门。