Targeting Sur1-Trpm4 in sepsis-induced brain injury

靶向 Sur1-Trpm4 治疗脓毒症引起的脑损伤

• 批准号: 10193865
• 负责人: RAJESH K. ANEJA
• 金额: $ 42.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193865
• 关键词: ATP-Binding Cassette Transporters; Acute; Address; Anatomy; Anisotropy; Antigens; Axon; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brain imaging; Cations; Cell Death; Cells; Clinical Management; Cognitive deficits; Complex; Critical Care; Data; Deterioration; Development; Diagnostic; Diagnostic radiologic examination; Diffusion; Edema; Encephalopathies; FDA approved; Family; Future; Genes; Glyburide; Guidelines; Health; Hippocampus (Brain); Immune system; Impaired cognition; Infection; Injury; Ion Channel; Knock-in Mouse; Knowledge; Light; Magnetic Resonance Imaging; Major Histocompatibility Complex; Mediating; Messenger RNA; Modeling; Morbidity - disease rate; Motor; Mus; Nervous System Physiology; Neuraxis; Organ; Outcome; Patient Care; Patients; Pattern; Pharmacology; Phase; Plasma; Pre-Clinical Model; Quality of life; Reporting; Role; Sepsis; Septic Shock; Shock; Sodium; Stroke; Sulfonylurea Compounds; Survivors; Swelling; TLR4 gene; Techniques; Thalamic structure; Time; Traumatic Brain Injury; Up-Regulation; Water; Wild Type Mouse; axon injury; base; behavioral outcome; cecal ligation puncture; central nervous system injury; cognitive performance; cytokine; cytotoxic; improved; improved outcome; inhibitor/antagonist; innovation; interest; mental state; neurofilament; neuroinflammation; novel; receptor; septic; septic patients; standard of care; sulfonylurea receptor; symptomatology; targeted treatment; therapeutic target; vasogenic edema; white matter damage

Abstract Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in long-term cognitive deficits, increased functional morbidity, and diminution in the quality of life. There are limited diagnostic adjuncts, and as no targeted therapy is available, clinical management of septic patients with central nervous system (CNS) symptomatology is limited to the treatment of the underlying infection and optimal critical care management of shock. Therefore, a better understanding of the pathobiology is needed to define acute brain derangements in sepsis. We have previously demonstrated that magnetic resonance imaging of the brain in mice subjected to cecal ligation and puncture (CLP) was notable for an early and marked decrease in fractional anisotropy consistent with axonal swelling and/or axonal injury that was associated with microglial activation, and the subsequent development of cytotoxic edema as evidenced by a significant decrease in apparent diffusion coefficient values four days after CLP. Sulfonylurea receptor -1(Sur1) is a transmembrane receptor in the ATP binding cassette transporter family ABCC8 that upregulates after CNS injury to form an obligate association with Ca2+ sensitive transient receptor potential melastatin-4 (Trpm4) resulting in edema. Our preliminary data demonstrate the upregulation of Sur1 in murine septic brains. In this proposal, in aim 1, we will determine the temporal correlation between Sur1-Trpm4 expression and edema in the murine septic brain. In aim 2, we will determine if inhibition of Sur1-Trpm4 is associated with a decrease in microglial activation and edema, thereby leading to a subsequent improvement in outcomes in a murine CLP model of sepsis. The availability of an FDA approved Sur1-Trpm4 inhibitor further raises interest in this approach.

摘要 脓毒症引起的脑损伤与精神状态的急性恶化有关，导致长期的 认知缺陷，功能障碍增加，生活质量下降。有有限的 诊断辅助，由于没有靶向治疗可用，败血症患者的临床处理中心 神经系统(CNS)症状学仅限于治疗基础感染和最佳 休克的重症监护管理。因此，需要对病原学有更好的了解才能确定 脓毒症中的急性脑错乱。我们之前已经证明了核磁共振成像 盲肠结扎和穿孔(CLP)小鼠的大脑以早期和明显的下降而显著 与小胶质细胞相关的轴突肿胀和/或轴突损伤一致的分数各向异性 激活，以及随后的细胞毒性水肿的发展，证据是显著减少 CLP后4天的表观扩散系数值。磺脲类药物受体-1(Sur1)是一种跨膜蛋白 三磷酸腺苷结合盒转运体家族中的受体ABCC8在中枢神经系统损伤后上调形成 与钙离子敏感的瞬时受体电位Melastatin-4(Trpm4)专有关联，导致水肿。 我们的初步数据表明，在脓毒症小鼠的脑中，Sur1的表达上调。在本提案中，在目标1中， 我们将确定在脓毒症小鼠中Sur1-Trpm4的表达与水肿之间的时间相关性 大脑。在目标2中，我们将确定Sur1-Trpm4的抑制是否与小胶质细胞减少有关 激活和水肿，从而导致随后改善小鼠CLP模型的结果 败血症。FDA批准的Sur1-Trpm4抑制剂的问世进一步提高了人们对这一方法的兴趣。