Neuroimmune Regulation of Acute Kidney Injury

急性肾损伤的神经免疫调节

• 批准号: 10453717
• 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/10453717
• 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; 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; 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.

抗击急性肾损伤(AKI)的进展需要新的和创新的方法来理解 AKI的发病机制。AKI会导致死亡，在某些情况下还会进展为终末期肾病。没有FDA批准的 治疗AKI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 关于免疫系统和神经系统之间的相互作用，以防御由 发炎。我们目前的建议是基于观察到的迷走神经刺激(VNS)激活 炎症反射途径，一种神经免疫回路，对维持免疫平衡至关重要。 据推测，支配肾脏的迷走神经传入纤维会立即将神经冲动传递到C1 低位脑干中的神经元，然后发出传出信号，终止于脾和其他器官 抑制炎症。神经科学的最新进展提供了精致的工具，将允许解开 控制炎症和AKI并为治疗提供基础的神经元过程。目标1将 验证选择性传入和传出迷走神经通过不同神经元介导肾脏保护的假说 小路。目标2将开始解开调节保护性抗炎反射的中央回路 通过测试C1神经元是否是连接传入和传出的中枢节点而引起传入VNS 四肢的炎症反射通路。一组低位脑干--C1神经元的作用 儿茶酚胺能/谷氨酸能神经元，在炎症反射途径和对AKI的保护作用 这一目标是我们研究的主要重点。C1神经元调节交感和副交感神经传出，并且 我们之前已经证明，刺激C1神经元也能保护小鼠免受AKI的伤害。目标3将重点放在 传出迷走神经的效应机制。这里我们假设传出迷走神经激活α7nAChR IgM-抗白细胞自身抗体(ALA)产生的B1淋巴细胞，对于阻止炎症和 阿琪。最后，我们将从24名暴露于VNS的人类受试者的完整研究中获取血浆样本 确定VNS(抑制促炎细胞因子--最初研究的重点)是否会增加血浆水平 免疫球蛋白M-丙氨酸(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前所未有的能力来定义特定的神经回路 来控制免疫力和炎症。这些研究利用了一个多学科团队，该团队包括 肾病学家、神经学家和免疫学家试图定义潜在炎症的路线图 保护肾脏免受IRI影响的反射通路。获得对基因和分子的理解，这是 控制炎症的迷走神经通路的多样性对于精确度的未来是必不可少的 生物电子医学。