Immune Mechanisms of Salt-Sensitive hypertension
盐敏感性高血压的免疫机制
基本信息
- 批准号:10210910
- 负责人:
- 金额:$ 71.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-04 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdoptive TransferAdultAmilorideAntigen-Presenting CellsAntigensAutologousBlood GlucoseBlood Plasma VolumeBlood PressureCalciumCardiovascular DiseasesCell physiologyCellsCessation of lifeCholesterolClinicConsumptionDataDendritic CellsDiagnosisDiagnosticDiagnostic testsDietary intakeElectrostaticsEssential HypertensionExcretory functionExposure toExtracellular FluidFutureGlycosaminoglycansGoalsHumanImmuneImmunodeficient MouseImmunologyIn VitroIndividualInfiltrationInflammationInpatientsInvestigationKidneyKnockout MiceLeadLipidsMagnetic Resonance ImagingMeasuresMediatingMusMuscleNADPH OxidaseOrganParticipantPathogenesisPatientsPersonsPhenotypePlayProliferatingProteinsProteomicsProtocols documentationPulse PressureRegulationResearchResistanceRisk FactorsRoleSamplingScientistSgk proteinSkinSodiumSodium ChlorideT-Cell ActivationT-LymphocyteTestingTherapeuticTissuesVascular DiseasesWateradductbasebench to bedsidecardiovascular risk factorcost effectivecytokinedietarydietary excessendothelial dysfunctionepithelial Na+ channelexperimental studygraft vs host diseasehigh body mass indexhumanized mouseimmune activationin vivoinsightinterstitialkidney dysfunctionmetabolomicsmonocytemortalityneoantigensnormotensiveoxidationpersonalized diagnosticspersonalized therapeuticpublic health relevancerenal damageresponsesalt intakesalt sensitivesalt sensitive hypertensionsuccesstherapy developmenttooltraittranscriptomicstranslational studywestern diet
项目摘要
Project Summary:
Salt-sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular mortality not only in
hypertensive, but also in normotensive adults. The diagnosis for SSBP is not feasible in the clinic due to lack of
a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to
understand the mechanisms of SSBP have focused on renal regulation of sodium (Na+). However, salt retention
or plasma volume expansion are not enhanced in salt sensitive (SS) versus salt resistant (SR) individuals. In
addition, over 70% of extracellular fluid is interstitial and therefore not directly controlled by renal salt and water
excretion. Thus, further research is needed to understand the extrarenal mechanisms contributing to SSBP.
We recently found that Na+ enters monocyte-derived dendritic cells through the amiloride sensitive epithelial Na+
channel (ENaC) and activates the NADPH oxidase leading to formation of highly reactive products of lipid
oxidation known as isolevuglandins (IsoLGs). IsoLGs adduct to self-proteins and act as neoantigens, which
activate T cells to produce cytokines that promote Na+ retention and blood pressure (BP) elevation. Interestingly,
analogous to SSBP, we found considerable variability in the response of human monocytes to in vitro exposure
to elevated Na+ which correlated with known cardiovascular risk factors. It is not known if this variability in the
responsiveness of monocytes to elevated Na+ happens in vivo and if it contributes to the SSBP.
Recent studies found that Na+ accumulates in the interstitium electrostatically bound to glycosaminoglycans but
can be mobilized. This is relevant to circulating monocytes as they enter and re-emerge from the interstitium with
increased ability to present antigens. Our data indicate that monocytes from humans with high skin Na+ are
activated and have increased IsoLGs. This R01 proposal presents an opportunity to study how immune activation
and interstitial Na+ interact to impact SSBP in well phenotyped SS and SR individuals. We hypothesize that
circulating monocytes transmigrate into regions of elevated Na+ including the skin, muscle and kidney, and are
activated via IsoLG-adduct formation leading to SSBP. In Aim 1, we will employ an inpatient Weinberger protocol
to classify participants as SS or SR and measure tissue Na+ using 23NaMRI to determine if tissue Na+ and
monocyte activation contribute to SSBP. In Aim 2, we will adoptively transfer monocytes with T cells from SS
and SR people into immunodeficient NSG-(KbDb)null (IA)null mice and determine if monocytes from humans with
SSBP induce T cell activation, endothelial dysfunction, end-organ damage and SSBP in the humanized mice.
These translational studies will advance the field and reveal more feasible and cost-effective diagnostic and
therapeutic strategies for SSBP. Our exciting preliminary data indicating that changes in monocyte IsoLGs mirror
changes in BP in response to salt provide promise for not only a simple diagnostic tool, but also mechanistic
insight into the pathogenesis of SSBP. Alongside efforts to develop therapies for SSBP by focusing on the kidney,
we propose that interstitial Na+ and monocyte activation via IsoLGs are important targets.
项目总结:
血压盐敏感性(SSBP)是心血管死亡的独立危险因素,不仅在
高血压,但血压正常的成年人也是如此。SSBP的诊断在临床上是不可行的,因为缺乏
一种简单的诊断测试,使研究治疗策略变得困难。大多数研究努力都是为了
对SSBP机制的认识主要集中在肾脏对钠(Na+)的调节。然而,盐分滞留
盐敏感(SS)患者与耐盐(SR)患者相比,血浆容量扩张并不增强。在……里面
此外,超过70%的细胞外液是间质的,因此不受肾盐和水的直接控制。
排泄物。因此,需要进一步的研究来了解SSBP的肾外机制。
我们最近发现,Na+通过阿米洛利敏感的上皮Na+进入单核细胞来源的树突状细胞
通道(ENaC)并激活NADPH氧化酶,导致高活性脂质产物的形成
氧化称为异uglandins(IsoLGs)。IsoLGs与自身蛋白质加成,作为新的抗原,它
激活T细胞产生细胞因子,促进钠离子滞留和血压升高。有趣的是,
与SSBP类似,我们发现人类单核细胞对体外暴露的反应有相当大的变异性
升高的Na+与已知的心血管危险因素相关。目前尚不清楚这一变化是否在
单核细胞对升高的Na+的反应性在体内发生,如果它对SSBP有贡献。
最近的研究发现,Na+在与糖胺聚糖静电结合的间质中积累,但
可以被动员起来。这与循环单核细胞进入和重新出现在间质中时有关。
提高了呈现抗原的能力。我们的数据表明,来自皮肤高钠离子的单核细胞
已激活并已增加等长。R01提案提供了一个机会来研究免疫激活如何
在表型良好的SS和SR个体中,间质Na+相互作用影响SSBP。我们假设
循环中的单核细胞转移到Na+升高的区域,包括皮肤、肌肉和肾脏,并
通过等LG加合物的形成激活,导致SSBP。在目标1中,我们将采用住院的Weinberger方案
将参与者分为SS或SR,并使用23NaMRI测量组织Na+,以确定组织Na+和
单核细胞活化参与了SSBP的发生。在目标2中,我们将过继地将单核细胞与SS中的T细胞一起转移
和SR人进入免疫缺陷NSG-(KbDb)Null(IA)缺失小鼠,并确定来自人类的单核细胞是否具有
SSBP可引起人源化小鼠T细胞活化、内皮功能障碍、终末器官损伤和SSBP。
这些翻译研究将推动该领域的发展,并揭示更可行和更具成本效益的诊断和
SSBP的治疗策略。我们令人兴奋的初步数据表明,单核细胞等电离散射镜的变化
BP对盐的反应变化不仅为一种简单的诊断工具提供了希望,也为机械诊断提供了希望
洞察SSBP的发病机制。在努力开发以肾脏为重点的SSBP治疗方法的同时,
我们认为,通过IsoLGs激活间质Na+和单核细胞是重要的靶点。
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)
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Annet Kirabo其他文献
Annet Kirabo的其他文献
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{{ truncateString('Annet Kirabo', 18)}}的其他基金
Salt taste sensitivity, genetics and salt sensitivity of blood pressure in HIV
HIV 患者的盐味敏感性、遗传和血压盐敏感性
- 批准号:
10748253 - 财政年份:2023
- 资助金额:
$ 71.14万 - 项目类别:
Deep phenotypic and functional characterization of salt-responsive immune cells in human salt senstive hypertension using CTE-seq
使用 CTE-seq 对人类盐敏感性高血压中的盐反应性免疫细胞进行深度表型和功能表征
- 批准号:
10337042 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Immune Mechanisms of Salt-Sensitive hypertension
盐敏感性高血压的免疫机制
- 批准号:
10401485 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Deep phenotypic and functional characterization of salt-responsive immune cells in human salt senstive hypertension using CTE-seq
使用 CTE-seq 对人类盐敏感性高血压中的盐反应性免疫细胞进行深度表型和功能表征
- 批准号:
10095170 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Immune Mechanisms of Salt-Sensitive hypertension
盐敏感性高血压的免疫机制
- 批准号:
10613511 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction
增强副交感神经活性,减少血管氧化应激和内皮功能障碍
- 批准号:
10418658 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction
增强副交感神经活性,减少血管氧化应激和内皮功能障碍
- 批准号:
10625349 - 财政年份:2021
- 资助金额:
$ 71.14万 - 项目类别:
Role of Salt, Isoketal-modified Proteins and Dendritic Cells in Hypertension
盐、异缩酮修饰蛋白和树突状细胞在高血压中的作用
- 批准号:
9014703 - 财政年份:2016
- 资助金额:
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ENaC regulation and its role in blood pressure homeostasis
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- 批准号:
10338091 - 财政年份:1996
- 资助金额:
$ 71.14万 - 项目类别:
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