Protective role of Neuregulin-1 against cerebral malaria-induced neuronal injury and behavioral sequelae

Neuregulin-1对脑型疟疾引起的神经元损伤和行为后遗症的保护作用

基本信息

批准号：
10541866
负责人：
BYRON D. FORD
金额：
$ 54.22万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541866
关键词：
3-Dimensional ANGPT1 gene Aftercare Algorithms Angiopoietin-2 Animal Model Animals Anti-Inflammatory Agents Antibodies Apoptosis Apoptotic Attenuated Autopsy Behavioral Blood - brain barrier anatomy Blood brain barrier dysfunction Brain Brain Edema Brain Injuries CD8-Positive T-Lymphocytes CD8B1 gene CXCL10 gene Cell Culture Techniques Cerebral Malaria Cerebrum Cessation of life Child Chimeric Proteins Clinical Trials Cognition Collaborations Coma Conscious Cytolysis Dendritic Cells Disease Encephalitis Epithelial Cells ErbB4 gene Erythrocytes Ethics Extracellular Matrix Falciparum Malaria Fatal Outcome Gene Expression Genes Goals HRP-2 protein Heart failure Heme Human Human Experimentation Impairment In Vitro Inbred BALB C Mice Induction of Apoptosis Infection Inflammasome Inflammation Inflammation Mediators Inflammatory Integration Host Factors Interferons Intravenous Magnetic Resonance Imaging Malaria Matrix Metalloproteinases Mediating Microcirculation Modeling Mus Neuregulin 1 Neuronal Injury Neuropeptides Organoids PD-1 blockade PD-1/PD-L1 Parasites Participant Pathogenesis Peptides Peripheral Blood Lymphocyte Phosphorylation Plasmodium berghei Plasmodium falciparum Predisposition Production Proto-Oncogene Proteins c-akt Recovery Regulatory Pathway Reporting Resistance Role STAT3 gene Serum Severities Severity of illness Signal Pathway Signal Transduction Survival Rate Survivors T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Agents Tissues Translating Urine artemether attenuation brain dysfunction brain endothelial cell brain tissue cell injury disease prognosis effectiveness evaluation genetic variant heme oxygenase-1 human stem cells human subject improved in vitro Model induced pluripotent stem cell monocyte mortality neglect neurobehavioral neurovascular unit programmed cell death ligand 1 programmed cell death protein 1 prospective receptor recruit tau Proteins

项目摘要

Human cerebral malaria (HCM) is a severe form of Plasmodium falciparum (P.f.) malaria associated with ~500,000 deaths in children annually and impaired brain function in some survivors. HCM is characterized by sequestration of parasitized red blood cells (pRBCs) in cerebral micro-circulation and induction of inflammatory mediators, brain swelling and impaired consciousness with unarousable coma. We have determined that circulating free heme and parasite histidine rich protein 2 (HRP2), by-products of pRBC lysis, are major causes of brain inflammation, blood-brain barrier (BBB) dysfunction, and brain injury associated with HCM. However, defining the mechanism(s) mediating these effects in HCM is challenging in the absence of suitable models. In vitro 2D cell culture, 3D brain organoid and animal models (ECM; Plasmodium berghei ANKA in C57BL/6) all indicate that heme and HRP2 induced cellular apoptosis, inflammation, and tissue disorganization. In ECM, heme causes brain vascular endothelial cell apoptosis, alters Angiopoietins 1 and 2 ratios, upregulates CXCL10, Heme Oxygenase 1, and tau as well as compromise BBB integrity through STAT3 signaling via matrix metalloproteinase three (MMP3). Following a screen for therapeutic agents against ECM, we identified Neuregulin- 1(NRG1), an 8 kDa neuropeptide currently undergoing clinical trials against heart failure, that attenuates ECM when delivered intravenously at 5µg/kg. NRG1 mediates phosphorylation of ErbB4 (receptor), activates AKT and inactivates STAT3 in human brain microvascular endothelial cells. ECM resistant mice (BALB/c) constitutively expressed higher levels of NRG1 in brain tissue than ECM susceptible (C57BL/6) mice. Since circulating NRG1 is severely depleted in both fatal HCM and ECM, levels of NRG1 need to be assessed prospectively to ascertain amounts needed for augmentation to mitigate HCM severity. Interestingly, CD8+Tcell PD1/PD-L1 signaling mediated ECM recovery and PD1 was upregulated by NRG1. Using a human stem cell- derived neurovascular unit (NVU; brain chip), ECM and human subjects, we will determine the mechanism by which NRG1 attenuates cerebral malaria. We hypothesize that therapeutic administration of NRG1 will attenuate heme and HRP2-induced NVU damage and ECM mortality via NRG1/ErbB4 and PD/PD-L1 signaling. Our objective is to functionally assess the key regulatory pathways mediated by NRG1 to attenuate ECM, and heme- and HRP2-induced NVU damage. The specific aims are: 1) to test the hypothesis that an algorithm, consisting of NRG1, heme, HRP2, and markers of neuronal injury and inflammation can predict HCM severity, mortality and neurobehavioral sequelae; 2) to test the hypothesis that NRG1/ErbB4 and PD1/PD-L1 signaling crosstalk protects against heme and HRP2-induced damage in human NVU; and 3) to test the hypothesis that NRG1 attenuates ECM brain injury and behavioral deficit via NRG1/ErbB4 and PD1/PD-L1 signaling. Understanding the role of NRG1 in cerebral malaria pathogenesis and sequelae in survivors will enable us to determine the feasibility of targeting NRG1 in clinical trials with the ultimate goal of improving the survival of children with HCM.

人脑疟疾（HCM）是恶性疟原虫（P.F.）疟疾的一种严重形式每年的儿童死亡约500,000人，某些生存中的大脑功能受损。 HCM的特征是在脑微循环和炎症诱导中的寄生红细胞（PRBC）的隔离介体，大脑肿胀和意识障碍，昏迷不可公开。我们已经确定 PRBC裂解的循环游离血红素和寄生虫组蛋白富含蛋白2（HRP2）是主要原因大脑感染，血脑屏障（BBB）功能障碍以及与HCM相关的脑损伤。然而，在没有合适模型的情况下，定义HCM中介导这些效应的机制是具有挑战性的。在体外2D细胞培养，3D脑器官和动物模型（ECM； C57BL/6中的Berghei plasmodium berghei anka）ast 在ECM中血红素会导致脑血管内皮细胞凋亡，改变Angiopietins 1和2的比例，上调CXCL10，血红素氧合酶1和tau以及通过矩阵通过STAT3信号折衷的BBB完整性金属蛋白酶三（MMP3）。遵循针对ECM的治疗剂的屏幕，我们确定了 Neuregulin-1（NRG1），目前正在接受针对心力衰竭的临床试验的8 kDa神经肽，当以5µg/kg静脉内递送ECM时，ECM会减弱ECM。 NRG1介导ERBB4（受体），，，激活AKT并使人脑微血管内皮细胞中的STAT3失活。 ECM抗性小鼠（BALB/c）脑组织中始终表达的NRG1水平高于ECM易感（C57BL/6）小鼠。由于循环NRG1在致命的HCM和ECM中都严重耗尽，因此需要评估NRG1的水平有趣的是，CD8+TCELL NRG1更新了PD1/PD-L1信号介导的ECM恢复和PD1。使用人类干细胞衍生的神经血管单元（NVU；脑芯片），ECM和人类受试者，我们将通过 NRG1减弱了脑疟疾。我们假设NRG1的治疗性给药会减弱血红素和HRP2通过NRG1/ERBB4和PD/PD-L1信号传导诱导NVU损伤和ECM死亡率。我们的目的是在功能上评估由NRG1介导的降低ECM的关键调节途径，以及血红素 - 和HRP2诱导的NVU损伤。具体目的是：1）检验一个算法的假设， NRG1，血红素，HRP2和神经元损伤和炎症的标记可以预测HCM严重程度，死亡率和神经行为后遗症； 2）检验NRG1/ERBB4和PD1/PD-L1信号传导串扰的假设防止人NVU中的血红素和HRP2诱导的损害； 3）检验NRG1的假设通过NRG1/ERBB4和PD1/PD-L1信号传导减轻ECM脑损伤和行为不足。理解 NRG1在脑疟疾发病机理和后遗症中的作用将使我们能够确定在临床试验中靶向NRG1的可行性，其最终目标是改善HCM儿童的生存率。