PROTECTIVE ROLE OF NEUREGULIN-1 AGAINST CEREBRAL MALARIA PATHOGENESIS AND MORTALITY

Neuregulin-1 对脑型疟疾发病机制和死亡率的保护作用

• 批准号: 9053182
• 负责人: Jonathan K. Stiles
• 金额: $ 31.06万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053182
• 关键词: ANGPT1 gene; Aftercare; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autopsy; Biological; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain region; C57BL/6 Mouse; CXCL10 gene; Catabolism; Cells; Cerebellum; Cerebral Malaria; Cerebrum; Child; Clinical Trials; Coculture Techniques; Coma; Conscious; Down-Regulation; Encephalitis; Endothelium; Enzymes; ErbB4 gene; Erythrocytes; Fatal Outcome; Functional disorder; Glioma; Goals; Heme; Hippocampus (Brain); Human; In Vitro; Inbred BALB C Mice; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Integration Host Factors; Intercellular adhesion molecule 1; Intervention; Malaria; Mediating; Modeling; Mus; Neuregulin 1; Neurologic; Outcome; Parasites; Pathogenesis; Pathology; Pathway interactions; Peptides; Plasmodium berghei; Plasmodium falciparum; Procedures; Production; Reporting; Resistance; Role; STAT3 gene; Serum; Severities; Severity of illness; Signal Pathway; Signal Transduction; Survivors; System; Testing; Therapeutic Intervention; Tight Junctions; Tissues; Traumatic Brain Injury; Up-Regulation; Western Blotting; artemether; attenuation; behavior test; brain endothelial cell; brain tissue; cerebrovascular; endothelial dysfunction; heme a; killings; mRNA Expression; mortality; neurobehavioral; protective effect; protein expression; public health relevance; receptor; receptor expression; small molecule; way finding

 DESCRIPTION (provided by applicant): Severe malaria kills about 900,000 children a year and impairs brain function in some survivors. Human CM (HCM) is a severe form of malaria characterized by sequestration of parasitized red blood cells (pRBCs) in cerebral micro-circulation and induction of inflammatory mediators which cause impaired consciousness with unarousable coma. We reported [PLoS One, 2012;7(3):e34280)] that excess production of heme, a by-product of Plasmodium berghei-damaged erythrocytes during infection, is a major cause of inflammation, loss of blood brain barrier (BBB) integrity and tissue damage associated with fatal experimental cerebral malaria (ECM) . Excess free heme induces up-regulation of STAT3 and CXCL10 whereas up-regulation of HO-1, an essential enzyme in heme catabolism, limits sequestration of pRBC, induction of inflammatory mediators and brain tissue damage caused by ECM. Following a screen for agents that attenuate ECM, we identified Neuregulin- 1(NRG-1), a 8 kDa peptide currently undergoing clinical trials for use against traumatic brain injury, that attenuates mortality, limits sequestration of pRBC, induces anti-inflammatory mediators and reduces brain tissue damage in ECM when delivered intravenously or intra-peritoneally at 5µg/kg (J Neuro,2014:11:9). NRG- 1 mediated attenuation of mortality was via perturbation of expression of a network of pro-inflammatory and anti-inflammatory factors during ECM pathogenesis. We observed that ECM resistant mice (BALB/c) constitutively expressed higher levels of NRG-1 in brain tissue than ECM susceptible (C57BL/6) mice. In human malaria, serum NRG-1 was higher in mild malaria cases but lowest in fatal HCM indicating a possible inhibitory role of infection on endogenous serum NRG-1 production. Expression of NRG-1 in brain tissue, on the other hand, was dependent on expression of ErbB4, a NRG-1 receptor, in damaged brain regions. Since NRG-1 negatively regulates STAT3 and CXCL10 (a key biological determinant of fatal ECM) and positively regulates HO-1, our goal is to functionally assess the key pathways perturbed by NRG-1 to attenuate ECM and HCM pathogenesis. Our main hypothesis is that NRG-1 attenuates CM mortality by down regulating CXCL10 and STAT3 activation and up regulating HO-1. The proposed study focuses on the mechanism by which NRG- 1 regulates the heme-STAT3-CXCL10-HO-1 system to protect against fatal ECM. Three specific aims are proposed. Specific Aim 1: will test the hypothesis that NRG-1 is essential for protection of brain microvascular endothelium and blood-brain barrier (BBB) against heme-induced damage in human CM pathogenesis. Specific Aim 2: will test the hypothesis that NRG-1 is essential for protection against ECM-induced CNS damage and neurobehavioral outcomes via heme-STAT3-CXCL10-HO-1 signaling pathway. Specific Aim 3: will test the hypothesis that NRG-1 attenuates severe HCM by restoring integrity of human blood-brain barrier. Understanding the protective effect of NRG-1 against CM pathogenesis and mortality will provide opportunities for discovery of a new class of small molecule adjunctive therapeutics and interventions against fatal CM.

 描述（由申请人提供）：严重的疟疾每年导致约 900,000 名儿童死亡，并损害一些幸存者的脑功能。人类 CM (HCM) 是一种严重的疟疾，其特征是脑微循环中寄生红细胞 (pRBC) 的隔离和炎症介质的诱导，导致意识受损和无法唤醒的昏迷。我们报道 [PLoS One, 2012;7(3):e34280)] 血红素（伯氏疟原虫感染期间受损的红细胞的副产品）的过量产生是与致命的实验性脑型疟疾 (ECM) 相关的炎症、血脑屏障 (BBB) 完整性丧失和组织损伤的主要原因。过量的游离血红素会诱导 STAT3 和 CXCL10 的上调，而 HO-1（血红素分解代谢中的一种必需酶）的上调会限制 pRBC 的隔离、炎症介质的诱导以及 ECM 引起的脑组织损伤。在筛选减弱 ECM 的药物后，我们发现了 Neuregulin-1(NRG-1)，这是一种 8 kDa 的肽，目前正在进行用于治疗创伤性脑损伤的临床试验，当以 5 µg/kg 静脉内或腹膜内给药时，它可以降低死亡率、限制 pRBC 的隔离、诱导抗炎介质并减少 ECM 中的脑组织损伤 （神经学杂志，2014：11：9）。 NRG-1 介导的死亡率降低是通过 ECM 发病过程中促炎和抗炎因子网络表达的扰动实现的。我们观察到，ECM 抗性小鼠 (BALB/c) 的脑组织中 NRG-1 的表达水平高于 ECM 易感小鼠 (C57BL/6)。在人类疟疾中，血清 NRG-1 在轻度疟疾病例中较高，但在致命性 HCM 中最低，表明感染可能对内源性血清 NRG-1 产生具有抑制作用。另一方面，脑组织中 NRG-1 的表达依赖于受损脑区域中 NRG-1 受体 ErbB4 的表达。由于 NRG-1 负向调节 STAT3 和 CXCL10（致命 ECM 的关键生物决定因素）并正向调节 HO-1，因此我们的目标是功能性评估 NRG-1 扰动的关键途径，以减弱 ECM 和 HCM 发病机制。我们的主要假设是 NRG-1 通过下调 CXCL10 和 STAT3 激活并上调 HO-1 来降低 CM 死亡率。拟议的研究重点是 NRG-1 调节血红素-STAT3-CXCL10-HO-1 系统以防止致命的 ECM 的机制。提出了三个具体目标。具体目标 1：将检验以下假设：在人类 CM 发病机制中，NRG-1 对于保护脑微血管内皮和血脑屏障 (BBB) 免受血红素诱导的损伤至关重要。具体目标 2：将测试以下假设：NRG-1 对于通过 heme-STAT3-CXCL10-HO-1 信号通路保护 ECM 诱导的 CNS 损伤和神经行为结果至关重要。具体目标 3：将检验 NRG-1 通过恢复人类血脑屏障的完整性来减轻严重 HCM 的假设。了解 NRG-1 对 CM 发病机制和死亡率的保护作用将为发现一类新的小分子辅助疗法和针对致命 CM 的干预措施提供机会。