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Regulation of brain endothelial integrity by angiotensin receptors as treatment for cerebral malaria

血管紧张素受体调节脑内皮完整性治疗脑型疟疾

基本信息

批准号：
10350640
负责人：
ANA RODRIGUEZ
金额：
$ 32.2万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350640
关键词：
AGTR2 gene Affect Agonist Angiotensin Receptor Angiotensins Antimalarials Apoptosis Binding Biological Assay Blood Blood - brain barrier anatomy Brain Brain Diseases Cardiovascular system Cause of Death Cells Cerebral Malaria Cessation of life Characteristics Complication Concentration Camps Development Disease model Edema Electrical Resistance Embryo Endothelial Cells Endothelium Erythrocytes Fingerprint Foundations Genetic Models Goals Hemorrhage Human Immunofluorescence Immunologic Impaired cognition In Vitro Individual Intercellular Junctions Knock-out Knockout Mice Life Maintenance Malaria Maps Mediating Modeling Mus Outcome Parasites Pathology Patients Permeability Pharmacology Plasmodium falciparum Pre-Clinical Model Predisposition Proteins Receptor Signaling Regulation Renin-Angiotensin System Role Second Messenger Systems Sequence Homology Signal Transduction Signaling Molecule Small Interfering RNA Syndrome Testing Therapy Clinical Trials Type 2 Angiotensin II Receptor Virulent Wild Type Mouse angiotensin I (1-7)antagonist arm beta catenin blood-brain barrier disruption brain endothelial cell brain tissue endothelial dysfunction experimental study in vitro Assay in vitro Model in vivo irbesartan kidney cell peptide analog pre-clinical prevent protective effect receptor response treatment effect

项目摘要

Summary. Cerebral malaria (CM) remains the most virulent and deadliest manifestation of malaria. It is caused by Plasmodium falciparum infected erythrocytes (iRBC) adhering to host brain endothelial cells and compromising the blood brain barrier. While available anti-malarial drugs are effective at clearing parasites from the blood, they do not have specific effects against CM. We have found that P. falciparum-iRBC induced disruption of human brain microvascular endothelial cell junctions was prevented by the activation of the angiotensin (Ang) II receptor type 2 (AT2), achieving protection of endothelial integrity. We also found that AT2 agonists are protective against experimental CM, and mice deficient in the AT2 receptor are more susceptible to this syndrome. However, over the last years, we have expanded the renin-angiotensin system by identifying additional receptors (Mas and MrgD) that are activated by agonists similar or equal to AT2 agonists, such as C21, Ang-(1-7) and Ang-(1-9). We could also show that these compounds are protective against P. falciparum-induced disruption of endothelial integrity. Thus, we hypothesize that activation of one, two, or all three receptors of the beneficial arm of the renin- angiotensin system protects brain endothelial cells from parasite-induced disruption of their barrier function. To identify which receptor(s) are key in the protection of endothelial integrity, we will first quantify the effect of Ang-(1-9), Ang-(1-7) and C21 in receptor-transfected HEK293 cells and in human and murine brain endothelial cells on intracellular signaling molecules, known to be regulated by the agonists and important in the maintenance of endothelial barrier integrity. Receptor blockers targeting different angiotensin receptors will be tested for their ability to block the intracellular signaling induced by the protective Ang peptides/analogues. Primary endothelial cells will be also targeted with siRNA against AT2 and/or Mas and/or MrgD to identify the responsible receptor(s) for the signaling effects. Finally, primary brain endothelial cells isolated from mice deficient in one, two or three receptors will be used as a genetic model to confirm the conclusions made from the pharmacological and siRNA experiments. We will then identify the receptors involved in the protection mediated by Ang-(1-9), Ang-(1-7), and C21 of brain endothelial cells from P. falciparum-induced endothelial disruption. We will use a pharmacological approach with the receptor antagonists and siRNA against the receptors to determine their effects on endothelial activation and junction integrity and on selected second messengers. Finally, we will test how treatment with Ang-(1-9), Ang-(1-7) and C21 affects the outcome of CM in wild-type and genetically deficient mice in one of the three receptors as well as double and triple knockouts. The main goal of this project is to identify the angiotensin receptor(s) that mediate protection of endothelial integrity during CM. Our results will lay the foundation for the development of agonists against this receptor(s) as adjunct therapy for CM and potentially for other diseases where brain endothelial integrity is compromised.

总结。脑型疟疾仍然是疟疾最具毒性和最致命的表现形式。它是