Neuroimmune Regulation of Acute Kidney Injury

急性肾损伤的神经免疫调节

基本信息

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
项目类别：
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

项目摘要

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 (AKI) 的进展需要新颖和创新的方法来了解 AKI 的发病机制 AKI 会导致死亡，并且在某些情况下会进展为 ESRD。 FDA 尚未批准该药物。用于治疗 AKI 的药物的一个重要领域是疾病的神经免疫调节。免疫系统和神经系统之间的相互作用，以防御由免疫系统引起的损伤我们目前的建议是基于迷走神经刺激（VNS）激活炎症的观察。炎症反射通路是一种神经免疫回路，对于维持免疫稳态至关重要。支配肾脏的迷走神经传入纤维立即将神经冲动传递至 C1 下脑干的神经元然后发送传出信号，终止于脾脏和其他器官神经科学的最新进展提供了可以解开炎症的精细工具。控制炎症和 AKI 并为治疗奠定基础的神经过程。检验选择性传入和传出 VNS 通过不同神经元介导肾脏保护的假设目标 2 将开始解开介导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心节点，由传入 VNS 引发四肢炎症反射通路中一组下脑干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中的作用以及对 AKI 的保护将是我们研究的主要焦点是 C1 神经元调节交感神经和副交感神经传出神经，以及我们之前已经表明，刺激 C1 神经元也可以保护小鼠免受 AKI 的影响。传出 VNS 的效应机制在这里我们发现传出 VNS 激活 α7nAChR 表达。产生 IgM 抗白细胞自身抗体 (ALA) 的 B1 淋巴细胞，对于阻止炎症和抑制炎症至关重要最后，我们将从一项对 24 名暴露于 VNS 的受试者进行的完整研究中获取血浆样本。确定 VNS（抑制促炎细胞因子 - 原始研究的焦点）是否会增加血浆水平 IgM-ALA（当前研究的重点）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这些研究利用了由以下人员组成的多学科团队。肾病学家、神经科学家和免疫学家致力于确定潜在炎症性疾病的路线图保护肾脏免受 IRI 影响的反射途径获得 IRI 基础的遗传和分子理解。控制炎症的迷走神经通路的多样性对于精准的未来至关重要生物电子医学。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Kidney Mentoring and Assessment Program for Students: a guide for engaging medical students in nephrology.

学生肾脏指导和评估计划：医学生学习肾脏病学的指南。

DOI：
发表时间：
2019-12
期刊：
影响因子：
4.6
作者：
Bayliss, George P;Cobb, Jason;Decker, Brian;Hellman, Richard;Vasavada, Nina;Mackelaite, Lina;Shadur, Craig;Ilori, Titilayo;Ibrahim, Tod;Leight, Katlyn;Hsiao, Li;Molitoris, Bruce A;Okusa, Mark D;Parker, Mark G;ASN Workforce Committee
通讯作者：
ASN Workforce Committee

Peritubular Capillary Oxygen Consumption in Sepsis-Induced AKI: Multi-Parametric Photoacoustic Microscopy.

脓毒症引起的 AKI 中的管周毛细血管耗氧量：多参数光声显微镜。