Neuroimmune Mechanisms Involved in the Pathogenesis of Hypertension and Renal Injury

项目总结 高血压是美国最流行的疾病之一，尽管它无疑有 多因素病因学，最近的研究支持免疫系统和慢性 发炎。我们必须了解可能调节这种炎症的机制，以便 确定新的治疗靶点。 胆碱能抗炎新途径与已建立的下丘脑-垂体-肾上腺(HPA) AXIS被认为在激活时抑制炎症。这两种内源性刺激 机制可能通过副交感迷走神经发生。为了研究这种神经免疫系统 串扰在防止慢性炎症发展方面很重要，慢性炎症会促进高血压， 我们采用系统性红斑狼疮(SLE)的疾病模型。SLE是一种慢性自身免疫性炎症性疾病 以高血压患病率高为特征的疾病，这可能是由慢性肾脏引起的 血管和实质炎症。研究表明，系统性红斑狼疮患者心脏功能减退 心率变异性，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的活性。 与系统性红斑狼疮胆碱能抗炎通路受损和HPA轴失调有关 这些潜在的关系是否在高血压的发病机制中起到重要作用 SLE的设置。建议的研究采用综合生理学方法，并辅之以 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 系统性红斑狼疮小鼠的慢性炎症和高血压的发展。 凯萨·马西斯博士与她的主要导师史蒂夫·米夫林博士一起制定了一个计划，以进行 在这项拨款申请中提出的研究。马西斯博士将通过以下方式增加她目前的实验室专业知识 从她的指导团队成员那里接受神经生理学方面的培训(米夫林博士和 和免疫生物学(哈里森博士和拉马卡博士)技术。指导团队将给出 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，以及 未来的拨款。马西斯博士还将对她的数据的解释和 手稿/赠款准备。总而言之，这项提案是一项协调一致的努力，旨在让马西斯博士 完善她的技能，让她接触一套新的技能，她可以用这些技能来确立自己作为 高血压领域。

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.