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:
  • 金额:
    $ 32.2万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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ANA RODRIGUEZ其他文献

ANA RODRIGUEZ的其他文献

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{{ truncateString('ANA RODRIGUEZ', 18)}}的其他基金

Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists
使用 AT2 受体激动剂针对脑型疟疾期间受损的脑内皮屏障功能
  • 批准号:
    10386279
  • 财政年份:
    2021
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of acute kidney injury in malaria - Resubmission - 1
疟疾急性肾损伤的机制 - 重新提交 - 1
  • 批准号:
    10318648
  • 财政年份:
    2020
  • 资助金额:
    $ 32.2万
  • 项目类别:
Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists
使用 AT2 受体激动剂针对脑型疟疾期间受损的脑内皮屏障功能
  • 批准号:
    10312024
  • 财政年份:
    2019
  • 资助金额:
    $ 32.2万
  • 项目类别:
Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists
使用 AT2 受体激动剂针对脑型疟疾期间受损的脑内皮屏障功能
  • 批准号:
    10741585
  • 财政年份:
    2019
  • 资助金额:
    $ 32.2万
  • 项目类别:
Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists
使用 AT2 受体激动剂针对脑型疟疾期间受损的脑内皮屏障功能
  • 批准号:
    10528244
  • 财政年份:
    2019
  • 资助金额:
    $ 32.2万
  • 项目类别:
Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists
使用 AT2 受体激动剂针对脑型疟疾期间受损的脑内皮屏障功能
  • 批准号:
    10536595
  • 财政年份:
    2019
  • 资助金额:
    $ 32.2万
  • 项目类别:
New Plasmodium Strategies to Modulate Inflammation
调节炎症的新疟原虫策略
  • 批准号:
    7933271
  • 财政年份:
    2009
  • 资助金额:
    $ 32.2万
  • 项目类别:
New Plasmodium Strategies to Modulate Inflammation
调节炎症的新疟原虫策略
  • 批准号:
    7657970
  • 财政年份:
    2008
  • 资助金额:
    $ 32.2万
  • 项目类别:
New molecules in malaria sporozoite-hepatocyte infection
疟疾子孢子-肝细胞感染的新分子
  • 批准号:
    6678501
  • 财政年份:
    2003
  • 资助金额:
    $ 32.2万
  • 项目类别:
New molecules in malaria sporozoite-hepatocyte infection
疟疾子孢子-肝细胞感染的新分子
  • 批准号:
    7012290
  • 财政年份:
    2003
  • 资助金额:
    $ 32.2万
  • 项目类别:

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