Neuroimmune Regulation of Acute Kidney Injury

急性肾损伤的神经免疫调节

• 批准号: 10681399
• 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/10681399
• 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; Ischemia; Kidney; Kidney Diseases; Leukocytes; Light; Limb structure; Link; Longevity; Lymphocyte; Maps; Measures; Mediating; Medicine; Methods; Molecular; Mus; Nerve; Nerve Fibers; Nervous System; 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 Reduction; Role; Sampling; Sepsis; Signal Transduction; Specificity; Spleen; Synaptic Transmission; System; Testing; Therapeutic; Therapeutic procedure; Tissues; Transgenic Organisms; United States; Vagotomy; Vagus nerve structure; alpha-bungarotoxin receptor; bioelectronics; cytokine; effective therapy; extracellular; hospitalization rates; human subject; immunoregulation; innovation; mortality; multidisciplinary; nerve supply; neural circuit; next generation; novel; novel therapeutic intervention; optogenetics; protective effect; protective pathway; 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.

对抗急性肾损伤（阿基）的进展需要新的和创新的方法来理解AKI的作用。 阿基的发病机制。阿基导致死亡，在某些情况下进展为ESRD。没有FDA批准的 用于治疗阿基的药物。治疗学的一个重要领域-疾病的神经免疫调节-是基于 在免疫系统和神经系统之间的相互作用，以抵御由 炎症我们目前的建议是基于观察迷走神经刺激（VNS）激活了 炎症反射通路，一种在维持免疫稳态中至关重要的神经免疫回路。 假设支配肾脏的迷走神经传入纤维将神经冲动立即传递到C1 下脑干的神经元，然后发出传出信号，终止于脾脏和其他器官， 阻止炎症。神经科学的最新进展提供了精细的工具， 神经元过程，控制炎症和阿基，并为治疗提供基础。目标1将 验证选择性传入和传出VNS通过不同的神经元介导肾脏保护的假设。 途径。目标2将开始解开调节保护性抗炎反射的中枢回路 通过测试C1神经元是否是连接传入和传出的中枢节点，由传入VNS引起 炎症反射通路的分支。C1神经元的作用，一组低脑干 炎性反射通路中的儿茶酚胺能/多巴胺能神经元和对阿基的保护作用将是 我们的研究主要集中在这一目标。C1神经元调节交感神经和副交感神经传出， 我们先前已经表明刺激C1神经元也保护小鼠免受阿基。目标3将侧重于 传出VNS效应器机制。在这里，我们假设传出VNS激活α 7 nAChR表达在 产生IgM-抗白细胞自身抗体（ALA）的B1淋巴细胞，这对阻断炎症和 阿基最后，我们将从24名暴露于VNS的人类受试者的已完成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）是否会增加血浆水平 IgM-ALA（当前研究的重点）。拟议的研究将使用光遗传学进行， 因为这些方法提供了前所未有的能力来定义特定的神经回路 控制免疫和炎症的细胞这些研究利用了一个多学科团队， 肾脏病学家、神经科学家和免疫学家，他们试图确定一个潜在的炎症反应的路线图， 保护肾脏免受IRI的反射途径。获得遗传和分子理解， 控制炎症的迷走神经通路的多样性对未来的精确性至关重要。 生物电子医学