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:10432585
- 负责人:
- 金额:$ 57.83万
- 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:ACE2AffectAgeAldosteroneAngiotensin IIBlood PressureBone MarrowBrainCX3CL1 geneCardiovascular DiseasesCardiovascular systemCell membraneCellsDOCADataDevelopmentDisintegrinsDrug TargetingExperimental ModelsGene DeletionGenetic ModelsGenetically Engineered MouseHeartHumanHypertensionHypothalamic structureIn VitroIndividualInflammationInflammatoryInterleukin-1 betaInterleukin-6KidneyKnockout MiceLeadMaintenanceMediatingMedicalMetalloproteasesMicrogliaMolecularMusNerveNeuronsOrganPeptidyl-Dipeptidase APhysiologicalPrevalenceProcessProteinsPublic HealthRegulationRenin-Angiotensin SystemReportingResistance developmentResistant HypertensionRisk FactorsRoleSignal TransductionSodium ChlorideStimulusSynapsesTNF geneTestingTimeTissuesTransgenic OrganismsUnited StatesUp-RegulationVasopressinsWaterWorkagedbaseblood 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.
在美国 55 岁及以上人群中,高血压 (HTN) 的患病率高达 55%
导致心血管疾病(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。脑肾素-血管紧张素系统(RAS)在脑中的作用
维持正常血压 (BP) 以及导致高血压的神经心血管失调
已经牢固地确立了。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,这些都会导致高血压。虽然我们小组和其他人进行了大量的过度表达研究,
已确定 ACE2(2 型血管紧张素转换酶)在预防进展方面的益处
并在实验模型中改进 HTN 的治疗,我们的小组是第一个证明 ADAM17
(一种解整合素和金属蛋白酶)介导神经源性 HTN 中 ACE2 的脱落,从而减少 ACE2
小鼠和人类的补偿活动。 ADAM17 介导的 ACE2 脱落,这是蛋白质
胞外域从质膜上裂解并分泌到周围环境中,此后被
在包括心脏和肾脏在内的许多组织中得到证实。 ADAM17 被认为通过介导神经炎症
可溶性 TNFα、IL-6 反式信号传导、CX3CL1 等细胞因子,但这一机制尚未在国内外研究
神经源性高血压。 DOCA-盐 HTN 与 TNFα、IL-6 水平升高和 ACE2 活性降低相关
在大脑中,从神经元中删除 ADAM17 会降低血压,恢复 ACE2 活性并降低亲
炎症细胞因子。尽管 ADAM17 被认为是炎症的主要药物靶点,
选择性抑制剂的开发失败了。最近的工作被认为是革命性的,表明 ADAM17
成熟受到大脑中菱形蛋白(神经元中的 iRhom1 和小胶质细胞中的 iRhom2)的严格调节,
为新颖的目标策略打开了大门。因此,我们假设针对 ADAM17 成熟
将逆转神经源性高血压的交感神经兴奋和神经炎症。我们将测试这个新的
战略目标有以下两个具体目标。
使用人类干细胞衍生的神经元和小胶质细胞的组合,独特的转基因和条件
敲除小鼠,选择性删除小胶质细胞中的 ADAM17 (Cx3Cr1ERT2-ADAM17tom) 并靶向
敲低神经元 (Rhom1) 或小胶质细胞 (iRhom2) 中 ADAM17 的成熟,这是该研究的直接目标
应用程序的目的是: 1) 了解 ADAM17 上调是如何在整个前交感神经网络中发生的;
2)评估ADAM17在神经炎症和小胶质细胞激活中的前馈作用; 3) 测试新的
防止 ADAM17 激活和耐药 HTN 发展的临床相关靶向策略。
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:
10608153 - 财政年份:2022
- 资助金额:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 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:
$ 57.83万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 57.83万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 57.83万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 57.83万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 57.83万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 57.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 57.83万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 57.83万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 57.83万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 57.83万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 57.83万 - 项目类别:
Miscellaneous Programs














{{item.name}}会员




