Novel Role of Interleukin-17 in Sympathetic Activation in Heart Failure

IL-17 在心力衰竭交感神经激活中的新作用

• 批准号: 10094628
• 负责人: Shunguang Wei
• 金额: $ 58.96万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-08 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094628
• 关键词: Address; Age; Animals; Astrocytes; Biochemistry; Blood Circulation; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Cerebrospinal Fluid; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Data; Deterioration; Development; Diabetes Mellitus; Disease; Elderly; Electrophysiology (science); Etanercept; Experimental Models; Functional disorder; Healthcare Systems; Heart Rate; Heart failure; Hormonal; Hospitalization; Hypertension; Hypothalamic structure; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interleukin Receptor; Interleukin-1 beta; Interleukin-17; Interleukin-6; Interleukins; Interruption; Intervention; Kidney; Lead; Link; Mediator of activation protein; Metabolic Diseases; Microglia; Modeling; Molecular Biology; Myocardial Infarction; Myocardial dysfunction; Nerve; Neurons; Neurosciences; Neurosecretory Systems; Obesity; Outcome; Pathogenesis; Patients; Peripheral; Pharmacologic Substance; Pharmacology; Plasma; Population; Production; Property; Public Health; Rattus; Research; Research Priority; Research Project Grants; Role; Severities; Signal Transduction; Systolic heart failure; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Work; base; chemokine; clinical development; cytokine; heart function; immune activation; immunocytochemistry; improved; infliximab; inhibitor/antagonist; innovation; insight; mortality; novel; paraventricular nucleus; protective effect; receptor; response; socioeconomics; targeted agent; therapy outcome

Heart failure (HF) is the most common reason for hospitalization and death among those older than 65 years, and statistic is projected to grow as our population ages. The socioeconomic impact of HF on our health care system is enormous. Development of innovative approaches to the treatment of HF is therefore a top research priority. Although inflammation and immune activation have been implicated in the pathophysiology of HF over the past two decades, the progress for development of new pharmaceutical agents targeting this mechanism was stagnant, especially given that several anti-cytokine clinical trials targeting a single effector cytokine at the peripheral manifestations of HF did not produce clinical benefits. Obviously, the inflammatory mechanisms underlying the pathogenesis of HF have not been challenged. The proposed project studying a role of brain interleukin (IL)-17A (previously known as IL-17) in advancing central inflammation, sympathetic activation and cardiac dysfunction will address the need for a better understanding of the inflammatory mechanisms in HF and provide a novel anti-cytokine approach in treating this devastating disease. The research plan was developed based on the intrinsic property of IL-17A and our compelling preliminary data: 1) IL-17A is a kay inflammatory regulator bridging immune responses and tissue inflammation; 2) It boosts the expression of a broad spectrum of inflammatory mediators in the brain and in the peripheral tissue and cells; 3) Systemic and central administration of IL-17A induced dramatic and long-lasting increases in blood pressure, heart rate and renal sympathetic nerve activity to the levels not seen by other pre-inflammatory cytokines; 4) levels of IL-17A in the plasma, cerebrospinal fluid, and paraventricular nucleus of hypothalamus (PVN, a key cardiovascular and autonomic center of the brain) are higher in a rat model of HF vs. in sham-operated (Sham) animals; and 5) Its receptor, IL-17RA, is highly expressed in the PVN and substantially upregulated in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, biochemistry and neuroscience in Sham and HF rats, this project will: 1) identify the role of IL-17A in advancing central inflammation in HF; 2) determine the inflammatory mechanisms whereby IL-17A triggers sympathetic activation in HF; 3) evaluate the protective effect of central interventions targeting the IL-17A signaling, alone or in combination with other cytokines in HF. The proposed research will target a master regulator of inflammation rather than a single effector cytokine as a novel anti-cytokine strategy in treating HF, and consider the synergistic actions of multiple cytokines as a potentially more effective means of ameliorating HF. The proposed studies will characterize a previously unrecognized role of brain IL-17A in sympathetic activation and test its potential as a target in treating cardiac dysfunction of HF. Completion of this research project will provide important insights into the anti-inflammation therapeutic strategy in HF and may carry the implication for other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.

心力衰竭(HF)是65岁以上老年人住院和死亡的最常见原因， 随着我们人口的老龄化，预计统计数据将会增长。心衰对我们医疗保健的社会经济影响 系统是巨大的。因此，开发治疗心力衰竭的创新方法是一项顶级研究 优先考虑。尽管炎症和免疫激活参与了心衰的病理生理过程。 在过去的二十年里，针对这一机制的新药物的开发进展 停滞不前，特别是考虑到几项针对单一效应细胞因子的抗细胞因子临床试验 心衰的外周表现并没有产生临床益处。显然，炎症机制 心力衰竭的发病机制尚未受到挑战。提出的研究大脑角色的项目 白介素17A(以前称为白介素17)在促进中枢性炎症、交感神经激活和 心功能不全将解决更好地了解心衰炎症机制的需要 并提供了一种新的抗细胞因子方法来治疗这种毁灭性的疾病。研究计划是 基于IL-17A的固有特性和我们令人信服的初步数据开发的：1)IL-17A是一种Kay 炎症调节因子在免疫反应和组织炎症之间架起桥梁；2)它促进 脑组织和外周组织和细胞中广泛的炎症介质；3)系统性和 中枢应用IL-17A可引起血压、心率和 肾交感神经活性达到其他炎症前细胞因子所未见的水平；4)IL-17A水平 在血浆、脑脊液和下丘脑室旁核(PVN)，一个关键的心血管 和大脑自主神经中枢)在心力衰竭大鼠模型中高于假手术(Sham)动物； 其受体IL-17RA在PVN中高表达，在HF中高表达。使用多方面的 方法包括电生理学、分子生物学、免疫细胞化学、药理学、生物化学 在Sham和HF大鼠中，该项目将：1)确定IL-17A在促进中枢 心衰的炎症反应；2)确定IL-17A触发交感神经激活的炎症机制 3)评估针对IL-17A信号转导的中央干预的保护效果，单独或在 与其他细胞因子在心力衰竭中的结合。这项拟议的研究将针对炎症的主要调节者。 而不是单一效应细胞因子作为治疗心力衰竭的新的抗细胞因子策略，并考虑 多种细胞因子的协同作用是一种潜在的更有效的改善心力衰竭的方法。这个 拟议的研究将表征一个以前未被认识到的脑IL-17A在交感神经激活和 检测其作为治疗心力衰竭心功能不全靶点的潜力。这项研究项目的完成将 为心力衰竭的抗炎治疗策略提供了重要的见解，并可能带来启示 用于其他心血管疾病，如高血压和代谢性疾病，如肥胖或糖尿病。