Control of Renal Inflammation in Hypertension

高血压患者肾脏炎症的控制

基本信息

批准号：
10405490
负责人：
KEISA WILLIAMS MATHIS
金额：
$ 54.24万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
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/10405490
关键词：
Acetylcholine Acetylcholinesterase Acetylcholinesterase Inhibitors Acute Adoptive Transfer Adult Affect Anti-Cholinergics Anti-Inflammatory Agents Antihypertensive Agents Applications Grants Autoimmune Autoimmune Diseases Autonomic Dysfunction Biological Availability Blood Blood Pressure Cardiovascular Diseases Cell Nucleus Cells Chronic Communication Data Dementia Development Disease Disease model FDA approved Fostering Galantamine Ganglionectomy Guidelines Health Healthcare Hypertension Immune Impairment In Vitro Inflammation Inflammatory Inflammatory Response Kidney Lead Left Measures Methods Modality Modeling Monitor Mus Nerve Neuroimmune Neuroimmunomodulation Neurons Operative Surgical Procedures Pathogenesis Pathway interactions Patients Peripheral Persons Pharmacology Physiology Play Publishing Regulation Resistance Resistant Hypertension Role Spleen Splenectomy Sympathectomy System Systemic Lupus Erythematosus T-Lymphocyte Techniques Technology Therapeutic Vagotomy Vagus nerve structure Work base blood pressure reduction cardiovascular risk factor chronic inflammatory disease cost designer receptors exclusively activated by designer drugs dorsal motor nucleus hypertensive immune function immunoregulation innovation mouse model nanoparticle neural circuit neurotransmission new therapeutic target novel prevent relating to nervous system resistance mechanism targeted delivery therapeutically effective therapy resistant vagus nerve stimulation

项目摘要

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.

项目概要到 2025 年，全球预计将有 16 亿人患有高血压。这个估计可能会更高最近修改的高血压指南涵盖了数百万额外的患者。什么是令人担忧的是，几乎 20% 的高血压患者对当前的治疗方法有抵抗力。更好的理解为了识别新的高血压发病机制，需要了解高血压发病机制的潜在机制。和有效的治疗策略。慢性肾脏炎症被怀疑是难治性高血压的致病机制。的目标该拨款提案旨在使用慢性炎症模型来检查肾脏炎症的控制疾病。系统性红斑狼疮（SLE）是一种慢性自身免疫性炎症，其中肾脏炎症 SLE 患者出现高血压之前；因此，它是一个合适的疾病模型阐明高血压炎症起源的机制。涉及内源性神经免疫调节系统，例如新型胆碱能抗炎途径在正常控制过度炎症的情况下。我们的数据表明，增强迷走神经到脾脏的功能通过全身药理学方法途径减少肾脏炎症和血压 SLE实验小鼠模型。基于此，我们假设活跃的神经免疫途径可以保护通过抑制肾脏炎症并防止后续发展来保护肾脏高血压。在该提案的目标 1 中，我们将确定迷走神经的中枢刺激是否通过化学遗传学和药理学技术通过胆碱能抗氧化剂减少肾脏炎症炎症途径，并且在 SLE 中具有抗高血压作用。这一目标的研究将阐明所涉及的中心核调节肾脏炎症，如果不加以控制，可能会导致 SLE 患者出现高血压。在目标 2 中，我们将确定是否通过阻断其节点来抑制胆碱能抗炎途径神经传递加剧 SLE 高血压。这一目标的研究将确定关键的神经/外周适当的神经免疫调节所必需的成分。在目标 3 中，我们将确定是否有内在的肾抗炎症通路与以脾脏为中心的胆碱能抗炎通路并行工作。研究于该目的将检查高血压肾免疫细胞中局部乙酰胆碱的抗炎潜力- 使用体外研究和创新的嗅探细胞技术来检测易患 SLE 的小鼠。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的肾脏炎症，并提供控制高血压和其他慢性炎症性疾病的肾脏炎症的治疗选择。