Targeting ADAM17 maturation in resistant hypertension.
靶向顽固性高血压中 ADAM17 的成熟。
基本信息
- 批准号:10608153
- 负责人:
- 金额:$ 54.93万
- 依托单位:
- 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:2022-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAldosteroneAngiotensin IIAngiotensinsAutonomic DysfunctionBlood PressureBone MarrowBrainCX3CL1 geneCardiovascular DiseasesCardiovascular systemCell membraneCellsDOCADataDevelopmentDisintegrinsDrug TargetingExperimental ModelsGene DeletionGenetic ModelsGenetically Engineered MouseGlutamatesHeartHumanHypertensionHypothalamic structureIn VitroIndividualInflammationInflammatoryInterleukin-1 betaInterleukin-6KidneyKnockout MiceLeadMaintenanceMediatingMedicalMetalloproteasesMicrogliaMolecularMusNerveNeuronsOrganPeptidyl-Dipeptidase APhysiologicalPrevalenceProcessProteinsPublic HealthRegulationRenin-Angiotensin SystemReportingResistance developmentResistant HypertensionRisk FactorsRoleSignal TransductionSodium ChlorideStimulusSynapsesTNF geneTestingTimeTissuesTransgenic OrganismsUnited StatesUp-RegulationVasopressinsWaterWorkabsorptionagedblood pressure reductionclinically relevantconditional knockoutcytokineexosomehuman stem cellshypertension treatmenthypertensiveimprovedin vivoinhibitorknock-downmortalityneurogenic hypertensionneuroinflammationnoveloverexpressionparaventricular nucleuspreventreceptorrhomboidsalt sensitive hypertensionvasoconstriction
项目摘要
With prevalence as high as 55% for individuals aged 55 and older in United States, hypertension (HTN) is a
major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an
increasingly important medical and public health issue. The role of the brain renin-angiotensin system (RAS) in
the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to HTN
has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased
sympathetic nerve activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release
and inflammation, all contributing to HTN. While numerous overexpression studies, from our group and others,
have established the benefits of ACE2 (Angiotensin Converting Enzyme type 2) in preventing the progression
and improving the treatment of HTN in experimental models, our group was the first to demonstrate that ADAM17
(A Disintegrin And Metalloprotease) mediates ACE2 shedding in neurogenic HTN, thus reducing ACE2
compensatory activity in mice and humans. ADAM17-mediated ACE2 shedding, a process by which the protein
ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu, has since been
confirmed in many tissues including heart and kidney. ADAM17 is thought to mediate neuroinflammation through
soluble TNFα, IL-6 trans-signaling, CX3CL1 and other cytokines, yet this mechanism has not been studied in
neurogenic HTN. DOCA-salt HTN is associated with increased levels of TNFα, IL-6 and reduced ACE2 activity
in the brain, while deletion of ADAM17 from neurons reduces BP, restores ACE2 activity and decreases pro-
inflammatory cytokines. Although ADAM17 is thought to be a major drug target for inflammation, the
development of selective inhibitors has failed. Recent work, deemed revolutionary, shows that ADAM17
maturation is tightly regulated by rhomboid proteins in the brain (iRhom1 in neurons and iRhom2 in microglia),
opening the door for novel targeting strategies. Accordingly, we hypothesize that targeting ADAM17 maturation
will reverse sympatho-excitation and neuro-inflammation in neurogenic HTN. We will test this new
targeting strategy in the following two specific aims.
Using a combination of human stem cells-derived neurons and microglia, unique transgenic and conditional
knockout mice, with selective deletion of ADAM17 in microglia (Cx3Cr1ERT2-ADAM17tom) and targeted
knockdown of ADAM17 maturation in neurons (Rhom1) or microglia (iRhom2), the immediate objectives of this
application are to: 1) Understand how ADAM17 upregulation takes place throughout pre-sympathetic networks;
2) Assess the feed-forward role of ADAM17 in neuro-inflammation and microglia activation; and 3) Test new
clinically-relevant targeting strategies to prevent ADAM17 activation and the development of resistant HTN.
高血压(HTN)在美国55岁及以上人群中的患病率高达55%,是一种
心血管疾病(CVD)和全球死亡率的主要危险因素,因此仍然是
日益重要的医疗和公共卫生问题。脑内肾素-血管紧张素系统(RAS)在血管紧张素系统中的作用
正常血压的维持和导致HTN的神经-心血管失调
已经站稳了脚跟。血管紧张素(Ang)-II通过其1型受体(AT1R)促进
交感神经活动、盐和水重吸收、血管收缩、醛固酮和加压素释放
和炎症,都是HTN的致病因素。虽然来自我们团队和其他人的大量过度表达研究,
已经确定了ACE2(血管紧张素转换酶2型)在防止进展中的好处
并在实验模型上改进了HTN的治疗,我们小组首先证明了ADAM17
去整合素和金属蛋白水解酶介导神经源性HTN中ACE2的脱落,从而减少ACE2
老鼠和人类的代偿活动。ADAM17介导的ACE2脱落,蛋白质通过这个过程
胞外结构域从质膜上被切割并分泌到周围环境中,自那以后
在包括心脏和肾脏在内的许多组织中得到证实。ADAM17被认为通过
可溶性肿瘤坏死因子α、IL-6反式信号转导、CX3CL1等细胞因子的作用机制尚未见文献报道。
神经源性HTN。DOCA-SALT HTN与肿瘤坏死因子α、IL-6水平升高和血管紧张素转换酶2活性降低相关
在大脑中,虽然从神经元中删除ADAM17会降低血压,恢复ACE2活性,并减少PRO-2
炎性细胞因子。尽管ADAM17被认为是治疗炎症的主要药物靶点,但
选择性抑制剂的开发已经失败。最近的研究,被认为是革命性的,表明ADAM17
成熟受到大脑中菱形蛋白的严格调控(神经元中的IRHOM1和小胶质细胞中的IRHOM2),
为新的目标策略打开了大门。因此,我们假设靶向ADAM17成熟
将逆转神经源性HTN的交感兴奋和神经炎症。我们将测试这一新的
目标定位策略有以下两个具体目标。
使用人类干细胞来源的神经元和小胶质细胞的组合,独特的转基因和有条件的
小胶质细胞ADAM17选择性缺失基因敲除小鼠(Cx3Cr1ERT2-ADAM17tom)并靶向
抑制ADAM17在神经元(Rhom1)或小胶质细胞(IRHOM2)中的成熟,这是这一研究的直接目标
应用是为了:1)了解ADAM17上调是如何在交感前网络中发生的;
2)评估ADAM17在神经炎症和小胶质细胞激活中的前馈作用;以及3)测试新的
临床相关的靶向策略,以防止ADAM17激活和耐药HTN的发展。
项目成果
期刊论文数量(0)
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 }}
ERIC D LAZARTIGUES其他文献
ERIC D LAZARTIGUES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('ERIC D LAZARTIGUES', 18)}}的其他基金
Targeting ADAM17 maturation in resistant hypertension.
靶向顽固性高血压中 ADAM17 的成熟。
- 批准号:
10432585 - 财政年份:2022
- 资助金额:
$ 54.93万 - 项目类别:
SARS-CoV-2 tropism in the brain and its relationship to COVID-19 pathogenesis
SARS-CoV-2 在大脑中的趋向性及其与 COVID-19 发病机制的关系
- 批准号:
10272724 - 财政年份:2021
- 资助金额:
$ 54.93万 - 项目类别:
COVID19: SARS-CoV-2 and ACE2 interaction in hypertension
COVID19:SARS-CoV-2 和 ACE2 在高血压中的相互作用
- 批准号:
10152313 - 财政年份:2021
- 资助金额:
$ 54.93万 - 项目类别:
COVID19: SARS-CoV-2 and ACE2 interaction in hypertension
COVID19:SARS-CoV-2 和 ACE2 在高血压中的相互作用
- 批准号:
10398819 - 财政年份:2021
- 资助金额:
$ 54.93万 - 项目类别:
Targeting ACE2 ubiquitination for hypertension
靶向 ACE2 泛素化治疗高血压
- 批准号:
10318183 - 财政年份:2019
- 资助金额:
$ 54.93万 - 项目类别:
Targeting ACE2 ubiquitination for hypertension
靶向 ACE2 泛素化治疗高血压
- 批准号:
10534148 - 财政年份:2019
- 资助金额:
$ 54.93万 - 项目类别:
New strategies to restore ACE2 compensatory activity in neurogenic hypertension
恢复神经源性高血压中 ACE2 代偿活性的新策略
- 批准号:
10266017 - 财政年份:2018
- 资助金额:
$ 54.93万 - 项目类别:
P7: BRAIN-TARGETED ACE2 OVEREXPRESSION AND BLOOD PRESSURE REGULATION
P7:针对大脑的 ACE2 过度表达和血压调节
- 批准号:
7959748 - 财政年份:2009
- 资助金额:
$ 54.93万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政策的情绪动态
- 批准号:
10108433 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
- 批准号:
MR/X034690/1 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Fellowship
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341426 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341424 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Continuing Grant
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
- 批准号:
24K13490 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
- 批准号:
EP/Z00022X/1 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
- 批准号:
MR/Y003365/1 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
- 批准号:
2335955 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
- 批准号:
AH/Y007549/1 - 财政年份:2024
- 资助金额:
$ 54.93万 - 项目类别:
Research Grant














{{item.name}}会员




