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.

治疗急性肾损伤（AKI）的进展需要新颖和创新的方法来理解其病因