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

• 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
• 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

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.

项目摘要 高血压是美国最普遍的疾病过程之一，虽然它无疑具有 多因素病因学，最近的研究支持免疫系统和慢性 炎症我们必须了解可能调节这种炎症的机制， 确定新的治疗靶点。 新的胆碱能抗炎通路和已建立的下丘脑-垂体-肾上腺（HPA） 轴被认为在激活时抑制炎症。刺激这两种内源性 这种机制可以通过副交感迷走神经发生。为了研究这种神经免疫 串扰在防止可促进高血压的慢性炎症的发展中是重要的， 我们利用疾病模型系统性红斑狼疮（SLE）。SLE是一种慢性自身免疫性炎症性疾病， 一种以高血压高患病率为特征的疾病，其可能由慢性肾脏疾病介导。 血管和实质炎症。研究表明，SLE患者的心脏功能下降， 心率变异性，这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减少迷走神经活动 导致SLE患者胆碱能抗炎通路受损和HPA轴失调， 这些潜在的关系是否实质上有助于高血压的发病机制， SLE的设置。拟议的研究采用综合生理学方法，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有助于 SLE小鼠中慢性炎症的发展以及由此导致的高血压。 博士凯萨马西斯已经制定了一个计划，沿着与她的主要导师，博士史蒂夫米夫林，进行 在本申请中提出的研究。马西斯博士将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（Mifflin博士和 坎宁安）和免疫生物学（哈里森博士和拉马尔卡）技术。指导团队将提供 指导如何使用她获得的工具来回答本赠款中提出的重要问题， 未来的赠款。马西斯博士还将获得对她的数据的解释的宝贵见解， 手稿/赠款准备。总的来说，这项提议是一项协调努力，使马西斯博士能够 完善她的技能，让她接触到一套新的技能，她可以用它来建立自己作为一个领导者， 高血压领域。