Neuroimmune Regulation of Acute Kidney Injury

急性肾损伤的神经免疫调节

• 批准号: 10020389
• 负责人: Mark Douglas Okusa
• 金额: $ 49.18万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020389
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Affect; Afferent Pathways; Anti-Inflammatory Agents; Area; Autoantibodies; B-Cell Activation; Brain Stem; Cells; Cessation of life; Chronic Kidney Failure; Clinical Trials; Colitis; Critical Illness; Cytoprotection; Development; Devices; Disease; Distal; Economics; Efferent Pathways; Electric Stimulation; End stage renal failure; Epilepsy; Exposure to; FDA approved; Fiber; Foundations; Future; Genetic; Glutamates; Goals; Grant; Hemorrhagic Shock; Homeostasis; Immune system; Immunity; Immunoglobulin M; Immunologics; Immunologist; Incidence; Inflammation; Inflammatory; Injury; Institutes; Ischemia; Kidney; Kidney Diseases; Lead; Leukocytes; Light; Limb structure; Link; Longevity; Lymphocyte; Maps; Measures; Mediating; Medicine; Methods; Molecular; Mus; Nerve; Nerve Fibers; Nervous system structure; Neural Pathways; Neuroimmune; Neuroimmunomodulation; Neurons; Neurosciences; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Peritoneal; Pharmacogenetics; Pharmacotherapy; Plasma; Procedures; Process; Proteins; Public Health; Reflex action; Regulation; Reperfusion Injury; Reperfusion Therapy; Rheumatoid Arthritis; Risk; Role; Sampling; Sepsis; Signal Transduction; Specificity; Spleen; Testing; Therapeutic; Therapeutic procedure; Tissues; Transgenic Organisms; United States; Vagotomy; Vagus nerve structure; alpha-bungarotoxin receptor; anti-IgM; base; combat; cytokine; effective therapy; extracellular; hospitalization rates; human subject; immunoregulation; innovation; mortality; multidisciplinary; nerve supply; neural circuit; next generation; novel; novel therapeutics; optogenetics; protective effect; relating to nervous system; renal ischemia; side effect; success; tool; vagus nerve stimulation

Advances in combating acute kidney injury (AKI) require novel and innovative approaches to understanding the pathogenesis of AKI. AKI leads to death and in some cases progression to ESRD. There are no FDA approved drugs for the treatment of AKI. An important area of therapeutics - neuroimmunomodulation of disease - is based upon the interaction between the immune system and the nervous system to defend against injury induced by inflammation. Our current proposal is based on the observation that vagus nerve stimulation (VNS) activates the inflammatory reflex pathway, a neuro-immune circuit that is critical in maintaining immunological homeostasis. Vagal afferent fibers that innervate the kidney are hypothesized to immediately transmit neural impulses to C1 neurons in the lower brainstem that then send efferent signals that terminate on the spleen and other organs to block inflammation. Recent advances in neuroscience provide refined tools that will permit disentanglement of neuronal processes that control inflammation and AKI and provide the foundation for therapeutics. Aim 1 will test the hypothesis that selective afferent and efferent VNS mediate kidney protection by distinct neuronal pathways. Aim 2 will begin unraveling the central circuitry that mediates the protective anti-inflammatory reflexes elicited by afferent VNS by testing whether C1 neurons are the central node linking the afferent and efferent limbs of the inflammatory reflex pathway. The role of C1 neurons, a group of lower brainstem catecholaminergic/glutamatergic neurons, in the inflammatory reflex pathway and protection from AKI will be the main focus of our studies in this aim. C1 neurons regulate both sympathetic and parasympathetic efferents, and we have previously showed that stimulating C1 neurons also protects mice against AKI. Aim 3 will focus on the effector mechanism of efferent VNS. Here we hypothesize that efferent VNS activates α7nAChR expressed on IgM-anti-leukocyte auto-antibody (ALA)-producing B1 lymphocytes, which are critical to block inflammation and AKI. Lastly, we will obtain plasma samples from a completed study of 24 human subjects exposed to VNS to determine if VNS (suppresses proinflammatory cytokines - focus of the original study) increases plasma levels of IgM-ALA (focus of the current study). The proposed studies will be conducted using optogenetics and pharmacogenetics because these approaches offer unprecedented capability to define specific neural circuits that control immunity and inflammation. These studies leverage a multidisciplinary team consisting of nephrologists, neuroscientists and immunologists that seek to define a road map of the underlying inflammatory reflex pathway that protects kidneys from IRI. Attaining genetic and molecular understanding that underlies the diversity of the vagus nerve pathways controlling inflammation is imperative for the future of precision bioelectronic medicine.

打击急性肾脏损伤（AKI）的进步需要新颖而创新的方法来理解 AKI的发病机理。 AKI导致死亡，在某些情况下导致ESRD的发展。没有FDA批准 治疗AKI的药物。治疗的重要领域 - 神经免疫调节 - 基于 在免疫系统与神经系统之间的相互作用后，以防御因受伤的伤害 炎。我们当前的建议基于这样的观察，即迷走神经刺激（VNS）激活了 炎症反射途径，这是一种神经免疫电路，对于维持免疫稳态至关重要。 假设神经支配肾脏的迷走神经传入纤维会立即将神经脉冲传递到C1 下部脑干中的神经元，然后发送有效信号，这些信号终止于脾脏和其他器官 阻断炎症。神经科学的最新进展提供了精致的工具，可以解散 控制注射和AKI并为治疗提供基础的神经元过程。目标1意志 检验以下假设，即选择性传入有效的VNS通过不同的神经元介导肾脏保护 途径。 AIM 2将开始揭开介导受保护的抗炎反射的中央电路 通过测试C1神经元是否是连接传入且有效的中心节点，由传入VN引起 炎症反射途径的四肢。 C1神经元的作用，一组较低的脑干 在炎症反射途径中，儿茶酚胺能/谷氨酸能神经元将是AKI的保护 我们研究的主要重点。 C1神经元调节交感神经和副交感的有效性，以及 我们以前已经表明，刺激C1神经元还可以保护小鼠免受AKI的侵害。 AIM 3将重点放在 有效VN的效应器机制。在这里，我们假设有效的VNS激活了在 Igm-抗核细胞自动抗体（ALA）产生的B1淋巴细胞，这对于阻止注射和注射至关重要 aki。最后，我们将从对暴露于VNS的24名人类受试者的完整研究中获得血浆样本 确定VNS（抑制促炎细胞因子 - 原始研究的重点）是否增加了血浆水平 IgM-Ala（当前研究的重点）。拟议的研究将使用光遗传学和 药物遗传学因为这些方法提供了定义特定神经回路的前所未有的能力 控制免疫和炎症。这些研究利用了一个由 寻求定义潜在炎症的路线图的肾脏科医生，神经科学家和免疫学家 反射途径可以保护孩子们免受IRI的侵害。获得基础的遗传和分子理解 对控制感染的迷走神经途径的多样性对于精确的未来至关重要 生物电子医学。