Control of Renal Inflammation in Hypertension

高血压患者肾脏炎症的控制

• 批准号: 10614551
• 负责人: KEISA WILLIAMS MATHIS
• 金额: $ 50.77万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614551
• 关键词: Acceleration; Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Adoptive Transfer; Adult; Affect; Anti-Inflammatory Agents; Antihypertensive Agents; Applications Grants; Autoimmune; Autoimmune Diseases; Autonomic Dysfunction; Biological Availability; Blood Pressure; Cardiovascular Diseases; Cell Nucleus; Cells; Chronic; Chronic Kidney Failure; Communication; Data; Dementia; Development; Disease; Disease model; FDA approved; Fostering; Galantamine; Ganglionectomy; Genetic; Guidelines; Health; Healthcare; Hypertension; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Kidney; Left; Measures; Mental Depression; Methods; Modality; Modeling; Monitor; Mus; Nerve; Neuroimmune; Neuroimmunomodulation; Neurons; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Physiology; Publishing; Regulation; Resistance; Resistant Hypertension; Role; Spleen; Splenectomy; Sympathectomy; System; Systemic Lupus Erythematosus; T-Lymphocyte; Techniques; Technology; Therapeutic; Vagotomy; Vagus nerve structure; Work; blood pressure reduction; cardiovascular risk factor; care burden; cholinergic; chronic inflammatory disease; cost; designer receptors exclusively activated by designer drugs; dorsal motor nucleus; efficacy evaluation; hypertensive; immune function; immunoregulation; innovation; mouse model; nanoparticle; neural; neural circuit; neurotransmission; new therapeutic target; novel; pharmacologic; prevent; protective pathway; resistance mechanism; targeted delivery; therapeutically effective; therapy resistant; vagus nerve stimulation

PROJECT SUMMARY By 2025, an estimated 1.6 billion people around the world will be hypertensive. This estimate may be higher given recently modified guidelines for hypertension that are inclusive of millions of additional patients. What is concerning is that almost 20% of all hypertensive patients are resistant to current therapies. Better understanding of the underlying mechanisms involved in the pathogenesis of hypertension is required in order to identify new and effective therapeutic strategies. Chronic renal inflammation is suspected to be a causal mechanism of resistant hypertension. The objective of this grant proposal is to examine the the control of renal inflammation using a model of chronic inflammatory disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory in which renal inflammation precedes the development of hypertension in SLE; therefore, it is an appropriate disease model to use to elucidate mechanisms involved in the inflammatory origins of hypertension. Endogenous neuro-immunoregulatory systems like the novel cholinergic anti-inflammatory pathway are involved in the normal control of excessive inflammation. Our data indicate that boosting this vagus nerve-to-spleen pathway via systemic pharmacological approaches reduces renal inflammation and blood pressure in an experimental mouse model of SLE. Based on this, we hypothesize that active neuroimmune pathways protect the kidney by suppressing renal inflammation and preventing the subsequent development of hypertension. In Aim 1 of this proposal, we will determine if central stimulation of the vagus nerve via both chemogenetic and pharmacological techniques reduces renal inflammation through the cholinergic anti- inflammatory pathway, and is antihypertensive in SLE. Studies in this aim will elucidate central nuclei involved in the regulation of renal inflammation that if left unchecked can result in hypertension in SLE. In Aim 2, we will determine whether inhibiting the cholinergic anti-inflammatory pathway by blocking its nodes of neurotransmission exacerbates SLE hypertension. Studies in this aim will determine critical neural/peripheral components necessary for proper neuroimmune regulation. In Aim 3, we will determine if an intrinsic renal anti- inflammatory pathway works in parallel with the spleen-centric cholinergic anti-inflammatory pathway. Studies in this aim will examine the anti-inflammatory potential of local acetylcholine in renal immune cells in hypertension- prone SLE mice using in vitro studies and innovative sniffer cell technoogy. Overall, the proposed studies will explain how homeostatic neuroimmune mechanisms control renal inflammation in health, as well as offer therapeutic options for controlling renal inflammation in hypertension and other chronic inflammatory diseases.

项目摘要 到2025年，估计全球有16亿人将是高血压。这个估计可能更高 给定最近修改的高血压指南，其中包括数百万患者。是什么 关于所有高血压患者中，几乎有20％对当前疗法具有抵抗力。更好的理解 为了识别新的 和有效的治疗策略。 怀疑慢性肾脏炎症是抗性高血压的因果机制。目的 该赠款提案是使用慢性炎症模型检查肾脏炎症的控制 疾病。全身性红斑狼疮（SLE）是一种慢性自身免疫性炎症，其中肾脏炎症 在SLE中高血压的发展之前；因此，它是一种适当的疾病模型 阐明与高血压炎症起源有关的机制。 内源性神经免疫调节系统（如新型胆碱能抗炎途径）涉及 在过度炎症的正常控制中。我们的数据表明，增强这种迷走神经到刺激性 通过全身药理方法的途径可减少肾脏炎症和血压 SLE的实验小鼠模型。基于这一点，我们假设活跃的神经免疫途径保护 肾脏通过抑制肾脏炎症并防止随后的发展 高血压。在本提案的目标1中，我们将确定是否通过两者都通过 化学和药理学技术可通过胆碱能抗 - 减少肾脏炎症 炎症途径，在SLE中具有抗高血压。以此目的的研究将阐明涉及的中央核 在调节肾脏炎症的情况下，如果未检查，则可能导致SLE的高血压。在AIM 2中，我们将 确定是否通过阻止其淋巴结来抑制胆碱能抗炎途径 神经传递加剧了SLE高血压。此目的的研究将确定关键的神经/周围 适当的神经免疫调节所需的组件。在AIM 3中，我们将确定是否固有的肾脏抗 炎症途径与以脾脏为中心的胆碱能抗炎途径并行。研究 该目的将检查局部乙酰胆碱在肾脏免疫细胞中的抗炎潜力 俯卧的SLE小鼠使用体外研究和创新的嗅探细胞技术学。总体而言，拟议的研究将 解释稳态神经免疫机制如何控制健康中的肾脏炎症，并提供 控制高血压和其他慢性炎症性疾病中肾脏炎症的治疗选择。

项目成果

Central Activation of the Cholinergic Anti-Inflammatory Pathway Improves Outcome in a Murine Model of Systemic Lupus Erythematosus.

胆碱能抗炎途径的中枢激活可改善系统性红斑狼疮小鼠模型的结果。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Mathis,KeisaW;Shimoura,CarolineG;Stubbs,Cassandra;Brooks,Calvin
• 通讯作者: Brooks,Calvin