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.
项目摘要:
血压盐敏感性(SSBP)是心血管死亡率的独立危险因素,
高血压,但也在血压正常的成年人。SSBP的诊断在临床上是不可行的,因为缺乏
这是一个简单的诊断测试,使得研究治疗策略变得困难。大多数研究工作,
了解SSBP的机制主要集中在肾脏对钠(Na+)的调节。然而,盐的保留
或血浆容量扩张在盐敏感(SS)个体与盐抗性(SR)个体中没有增强。在
此外,超过70%的细胞外液是间质性的,因此不直接受肾盐和水的控制
排泄因此,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,导致形成高反应性脂质产物
氧化称为异evuglandins(IsoLGs)。异LG加合到自身蛋白质上并作为新抗原,
激活T细胞以产生促进Na+潴留和血压(BP)升高的细胞因子。有趣的是,
与SSBP类似,我们发现人单核细胞对体外暴露的反应存在相当大的变异性
与已知的心血管危险因素相关的Na+升高。目前尚不清楚这种变异性是否
单核细胞对升高的Na+的反应性在体内发生,并且如果其有助于SSBP。
最近的研究发现,Na+在与糖胺聚糖静电结合的胶体中积累,
可以动员起来。这与循环单核细胞有关,因为它们进入并从单核细胞中重新出现,
提高抗原呈递能力。我们的数据表明,来自皮肤Na+水平高的人的单核细胞,
激活并增加了IsoLGs。这个R 01提案提供了一个研究免疫激活如何的机会
在表型良好的SS和SR个体中,Na+和间质Na+相互作用影响SSBP。我们假设
循环单核细胞迁移到Na+升高的区域,包括皮肤、肌肉和肾脏,
通过形成IsoLG-加合物活化,导致SSBP。在目标1中,我们将采用住院患者Weinberger方案
将受试者分类为SS或SR,并使用23 NaMRI测量组织Na+,以确定组织Na+和
单核细胞活化有助于SSBP。目的2:将单核细胞与SS的T细胞过继转移,
和SR人的免疫缺陷NSG-(KbDb)null(IA)null小鼠中,并确定来自具有
SSBP诱导人源化小鼠T细胞活化、内皮功能障碍、终末器官损伤和SSBP。
这些转化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治疗方法。
SSBP的治疗策略我们令人兴奋的初步数据表明,单核细胞IsoLGs的变化反映了
血压对盐的反应变化不仅提供了一种简单的诊断工具,
了解SSBP的发病机制。除了通过关注肾脏来开发SSBP的治疗方法外,
我们提出间质Na+和单核细胞通过IsoLGs活化是重要的靶点。
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:
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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:
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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:
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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
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10338091 - 财政年份:1996
- 资助金额:
$ 71.14万 - 项目类别:
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