Neuroimmune Mechanisms Involved in the Pathogenesis of Hypertension and Renal Injury

高血压和肾损伤发病机制中涉及的神经免疫机制

基本信息

批准号：
10078626
负责人：
KEISA WILLIAMS MATHIS
金额：
$ 15.39万
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：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078626
关键词：
Animals Anti-Cholinergics Anti-Inflammatory Agents Antiinflammatory Effect Applications Grants Autoimmune Blood Blood Pressure Cardiovascular Diseases Cell Separation Cells Chronic Complement Conscious Data Data Analyses Depressed mood Development Disease Disease model Dissection Etiology Exposure to FOS gene Functional disorder Future Gap Junctions Glomerulonephritis Grant High Prevalence Hydrocortisone Hypertension Immune Immune response Immune system Immunobiology Immunologic Techniques Impairment In Situ Hybridization Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Kidney Laboratories Lasers Lead Link Manuscripts Measurement Mediating Mentors Microscopy Mus Nerve Nervous system structure Neuroimmune Neuroimmunomodulation Neurosecretory Systems Nicotinic Receptors Organ Parasympathetic Nervous System Pathogenesis Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacology Physiological Plasma Play Preparation Prevalence Process Protocols documentation Renal Blood Flow Role Severity of illness Signal Transduction Spleen Stains Systemic Lupus Erythematosus T-Lymphocyte Techniques Testing Training Vagus nerve structure Woman blood flow measurement blood pressure reduction cardiovascular risk factor clinically relevant cohort combat cytokine designer receptors exclusively activated by designer drugs heart rate variability human disease hypothalamic-pituitary-adrenal axis immune function immunocytochemistry improved indexing insight interdisciplinary approach interest kidney vascular structure macrophage member mouse model neurophysiology new therapeutic target novel prevent skills stressor tool

项目摘要

PROJECT SUMMARY Hypertension is one of the most prevalent disease processes in the US and, while it undoubtedly has a multifactorial etiology, recent studies support a prominent role for the immune system and chronic inflammation. It is critical that we understand mechanisms that may regulate this inflammation in order to identify new therapeutic targets. The novel cholinergic anti-inflammatory pathway and the established hypothalamic-pituitary-adrenal (HPA) axis are thought to suppress inflammation upon activation. Stimulation of both of these endogenous mechanisms may occur through the parasympathetic vagus nerve. To study whether this neuro-immune crosstalk is important in preventing the development of chronic inflammation that can promote hypertension, we utilize the disease model systemic lupus erythematosus (SLE). SLE is a chronic autoimmune inflammatory disorder characterized by a high prevalence of hypertension, which may be mediated by chronic renal vascular and parenchymal inflammation. Studies have demonstrated that SLE patients have decreased heart rate variability, which indicates impaired autonomic function. Specifically vagal nerve activity is depressed and this correlates with SLE disease severity. It is not known whether this decreased vagal nerve activity contributes to an impaired cholinergic anti-inflammatory pathway and HPA axis dysregulation in SLE, nor whether these potential relationships contribute substantially to the pathogenesis of hypertension in the setting of SLE. The proposed studies utilize an integrative physiological approach, complemented by neurophysiological and immunological techniques, to determine whether vagal dysfunction contributes to the development of chronic inflammation and consequently hypertension in SLE mice. Dr. Keisa Mathis has developed a plan along with her primary mentor, Dr. Steve Mifflin, to conduct the studies proposed within this grant application. Dr. Mathis will add to her current laboratory expertise by receiving training from members of her mentoring team in both neurophysiological (Drs. Mifflin and Cunningham) and immunobiological (Drs. Harrison and LaMarca) techniques. The mentoring team will give guidance on how to use her acquired tools to answer the important questions proposed in this grant and future grants. Dr. Mathis will also gain valuable insight into the interpretation of her data and manuscript/grant preparation. Taken together, this proposal is a coordinated effort to allow Dr. Mathis to refine her skills and to expose her to a new set of skills that she can use to establish herself as a leader in the field of hypertension.

项目概要高血压是美国最普遍的疾病之一，尽管它无疑具有多因素病因学，最近的研究支持免疫系统和慢性病的重要作用炎。至关重要的是，我们了解可能调节这种炎症的机制，以便确定新的治疗靶点。新型胆碱能抗炎通路和已建立的下丘脑-垂体-肾上腺（HPA）轴被认为可以在激活后抑制炎症。对这两种内源性的刺激机制可能通过副交感迷走神经发生。研究这种神经免疫是否串扰对于预防可促进高血压的慢性炎症的发展很重要，我们利用系统性红斑狼疮（SLE）疾病模型。 SLE是一种慢性自身免疫性炎症以高血压患病率高为特征的疾病，可能是由慢性肾病介导的血管和实质炎症。研究表明SLE患者心脏功能下降速率变异性，表明自主神经功能受损。特别是迷走神经活动受到抑制这与 SLE 疾病的严重程度相关。目前尚不清楚这是否会降低迷走神经活动导致系统性红斑狼疮 (SLE) 胆碱能抗炎通路受损和 HPA 轴失调，这些潜在的关系是否对高血压的发病机制有重大影响 SLE 的设置。拟议的研究利用综合生理学方法，并辅以神经生理学和免疫学技术，以确定迷走神经功能障碍是否导致 SLE 小鼠中慢性炎症的发展以及随之而来的高血压。凯萨·马蒂斯 (Keisa Mathis) 博士与她的主要导师史蒂夫·米夫林 (Steve Mifflin) 博士一起制定了一项计划，以开展本拨款申请中提出的研究。 Mathis 博士将通过以下方式增加她目前的实验室专业知识：接受她的指导团队成员在神经生理学方面的培训（米夫林博士和 Cunningham）和免疫生物学（Harrison 博士和 LaMarca 博士）技术。辅导团队将给予关于如何使用她获得的工具来回答这笔赠款中提出的重要问题的指导，以及未来的补助金。马蒂斯博士还将获得对其数据的解释的宝贵见解，以及手稿/资助准备。总而言之，该提案是一项协调一致的努力，使马西斯博士能够完善她的技能并让她接触一套新技能，她可以利用这些技能使自己成为该领域的领导者高血压领域。