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
- 来源:
- 关键词:AGTR2 geneAffectAgonistAngiotensin ReceptorAngiotensinsAntimalarialsApoptosisBindingBiological AssayBloodBlood - brain barrier anatomyBrainBrain DiseasesCardiovascular systemCause of DeathCellsCerebral MalariaCessation of lifeCharacteristicsComplicationConcentration CampsDevelopmentDisease modelEdemaElectrical ResistanceEmbryoEndothelial CellsEndotheliumErythrocytesFingerprintFoundationsGenetic ModelsGoalsHemorrhageHumanImmunofluorescence ImmunologicImpaired cognitionIn VitroIndividualIntercellular JunctionsKnock-outKnockout MiceLifeMaintenanceMalariaMapsMediatingModelingMusOutcomeParasitesPathologyPatientsPermeabilityPharmacologyPlasmodium falciparumPre-Clinical ModelPredispositionProteinsReceptor SignalingRegulationRenin-Angiotensin SystemRoleSecond Messenger SystemsSequence HomologySignal TransductionSignaling MoleculeSmall Interfering RNASyndromeTestingTherapy Clinical TrialsType 2 Angiotensin II ReceptorVirulentWild Type Mouseangiotensin I (1-7)antagonistarmbeta cateninblood-brain barrier disruptionbrain endothelial cellbrain tissueendothelial dysfunctionexperimental studyin vitro Assayin vitro Modelin vivoirbesartankidney cellpeptide analogpre-clinicalpreventprotective effectreceptorresponsetreatment 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.
摘要脑型疟疾(CM)仍然是最致命和最致命的疟疾表现。是
由恶性疟原虫感染的红细胞(iRBC)粘附于宿主脑内皮细胞引起,
危及血脑屏障虽然现有的抗疟疾药物在清除寄生虫方面是有效的,
从血液中分离出来,它们对CM没有特异性作用。
我们已经发现恶性疟原虫-iRBC诱导人脑微血管内皮细胞的破坏
血管紧张素(Ang)II受体2型(AT 2)的激活阻止了连接,
保护内皮完整性。我们还发现AT 2激动剂对实验性CM具有保护作用,
而缺乏AT 2受体的小鼠更容易患上这种综合征。然而,在过去的几年里,我们
已经通过鉴定额外的受体(Mas和MrgD)扩展了肾素-血管紧张素系统,
由类似或等同于AT 2激动剂的激动剂如C21、Ang-(1-7)和Ang-(1-9)激活。我们也可以
表明这些化合物对恶性疟原虫诱导的内皮完整性破坏具有保护作用。
因此,我们假设,激活一个,两个,或所有三个受体的有益臂的肾素-血管紧张素转换酶-
血管紧张素系统保护脑内皮细胞免受寄生虫诱导的屏障功能破坏。
为了鉴定哪种受体在保护内皮完整性中是关键的,我们将首先量化
受体转染的HEK 293细胞以及人和小鼠脑内皮细胞中的Ang-(1-9)、Ang-(1-7)和C21
细胞内信号分子,已知由激动剂调节,并在
维持内皮屏障的完整性。靶向不同血管紧张素受体的受体阻断剂将是
测试它们阻断由保护性Ang肽/类似物诱导的细胞内信号传导的能力。
还将用针对AT 2和/或Mas和/或MrgD的siRNA靶向原代内皮细胞,以鉴定内皮细胞的功能。
负责信号传导作用的受体。最后,从小鼠分离的原代脑内皮细胞
缺乏一个,两个或三个受体将被用作遗传模型,以证实从
药理学和siRNA实验。然后我们将识别出参与保护的受体
由恶性疟原虫诱导的脑内皮细胞的Ang-(1-9)、Ang-(1-7)和C21介导的
破坏我们将使用受体拮抗剂和siRNA的药理学方法来对抗
受体,以确定其对内皮活化和连接完整性以及对所选第二
使者最后,我们将测试用Ang-(1-9)、Ang-(1-7)和C21治疗如何影响CM的结果。
在野生型和遗传缺陷小鼠中,三种受体之一以及双重和三重敲除。
本项目的主要目标是鉴定介导内皮细胞保护的血管紧张素受体。
CM期间的完整性。我们的研究结果将为开发抗该受体的激动剂奠定基础
作为CM的辅助治疗,并可能用于脑内皮完整性受损的其他疾病。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ANA RODRIGUEZ其他文献
ANA RODRIGUEZ的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10536595 - 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:
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:
7012290 - 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:
6678501 - 财政年份:2003
- 资助金额:
$ 32.2万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 32.2万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 32.2万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 32.2万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 32.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists