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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.

人脑型疟疾（HCM）是与恶性疟原虫（P.f）相关的一种严重形式的疟疾