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。高血压在退伍军人事务部也非常普遍