Innate Immune Mediated Changes in Renal Function to Cause Hypertension in Females with Autoimmune Disease
先天免疫介导的肾功能变化导致患有自身免疫性疾病的女性高血压
基本信息
- 批准号:10714533
- 负责人:
- 金额:$ 33.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAntibody titer measurementAntigensAntioxidantsAttenuatedAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmunityAutomobile DrivingAwarenessBlood PressureBlood VesselsC-reactive proteinCardiovascular DiseasesCell surfaceCellsCellular StressChronicClinicalClinical DataClinical MarkersComplementDataDatabasesDevelopmentDiseaseErythrocyte Sedimentation RateEssential HypertensionExhibitsFemaleGenerationsGeneticGenetic ModelsHMGB1 geneHeat shock proteinsHumanHypertensionImmuneImmune systemImmunoglobulinsImmunologicsImmunosuppressionImmunotherapyImpairmentInflammasomeInflammationInformaticsInfrastructureInnate Immune ResponseKidneyKidney DiseasesLaboratoriesLigandsLinkLiteratureLow PrevalenceLupusLymphocyteMeasuresMediatingMethodsMitochondriaModelingMusNatural ImmunityObesityOxidative StressPathogenicityPathway interactionsPharmacotherapyPhysiologicalPopulationPrevalenceProductionPublishingReactive Oxygen SpeciesRenal functionRheumatismRheumatoid FactorRiskRoleRuralSerumSignal TransductionSodiumSourceSystemic Lupus ErythematosusTLR4 geneTestingTissuesTubular formationUnited States Department of Veterans AffairsUric AcidWomanabsorptioncardiovascular risk factorcell typeclinical data repositorycohortextracellularhuman modelimprovedin vivoinflammatory markerinnovationinsightkidney vascular structuremenmitochondrial dysfunctionmortalitymouse modelneutrophilnovelpharmacologicyoung woman
项目摘要
Primary hypertension is linked with immunological changes, including autoantibody production, that are
consistent with autoimmune underpinnings of hypertension. The innate immune response also has a central role
in the development of autoimmunity; however, the mechanistic contributions of innate immunity to autoimmune
associated hypertension have not been studied. This proposal will examine a novel innate immune feedforward
mechanism that promotes hypertension during systemic lupus erythematosus (SLE), a disorder that
predominantly affects young women, thus significantly advancing the field towards a better understand of
immune mediated hypertension. We previously showed that an experimental female mouse model of human
SLE exhibits impaired renal vascular function and sodium handling, renal oxidative stress, and hypertension that
is ameliorated by antioxidants. Despite this, little is understood about the cellular sources of reactive oxygen
species or the intracellular pathways that drive changes in renal function during SLE associated hypertension.
The innate immune response has an important role in causing tissue damage during SLE. This proposal will
test the central hypothesis that during SLE there is a feedforward mechanism driving the generation of renal
ROS, leading to impaired renal vascular function and increased tubular sodium reabsorption. This cycle involves
the presence of NETs that increase cell stress signals, including HMGB1, TLR4 mediated mitochondrial
dysfunction, and the production of ROS. Mitochondrial ROS activate the NLRP3 inflammasome, which
perpetuates the cycle by promoting further generation of NETs to induce additional cell stress. This will be tested
in three aims (1) During SLE, NETs promote hypertension by increasing renal ROS that causes impaired renal
vascular and tubular function. (2) During SLE, cell stress proteins (HMGB1) increase mitochondrial ROS
generation leading to NLRP3 inflammasome activation and further NET production through a TLR4 mediated
mechanism. (3) A large data cohort (approximately 32,000) from men and women with SLE will be examined for
relationships between clinical markers of inflammation, immunotherapies, and blood pressure. The proposal
uses widely established models of SLE, an innovative genetic model, state-of-the-art physiological,
pharmacological, and immunological methods, along with a national data base of human clinical data to
rigorously test these aims.
原发性高血压与免疫变化有关,包括自身抗体的产生,
与高血压的自身免疫基础一致。先天免疫反应也发挥着核心作用
自身免疫的发展;然而,先天免疫对自身免疫的机制贡献
尚未研究相关高血压。该提案将研究一种新型的先天免疫前馈
系统性红斑狼疮 (SLE) 期间促进高血压的机制,这种疾病
主要影响年轻女性,从而显着推动该领域更好地理解
免疫介导的高血压。我们之前表明,人类的实验性雌性小鼠模型
SLE 表现出肾血管功能和钠处理功能受损、肾氧化应激和高血压,
可以通过抗氧化剂来改善。尽管如此,人们对活性氧的细胞来源知之甚少。
SLE 相关高血压期间驱动肾功能变化的物种或细胞内途径。
先天免疫反应在系统性红斑狼疮期间造成组织损伤中发挥着重要作用。该提案将
检验中心假设,即在 SLE 期间,存在驱动肾细胞生成的前馈机制
ROS,导致肾血管功能受损和肾小管钠重吸收增加。这个循环涉及
NET 的存在会增加细胞应激信号,包括 HMGB1、TLR4 介导的线粒体
功能障碍和 ROS 的产生。线粒体 ROS 激活 NLRP3 炎症小体,
通过促进 NET 的进一步产生来诱导额外的细胞应激,从而使循环永久化。这将被测试
三个目标 (1) 在 SLE 期间,NET 通过增加肾 ROS 来促进高血压,从而导致肾功能受损
血管和肾小管功能。 (2) SLE期间,细胞应激蛋白(HMGB1)增加线粒体ROS
产生导致 NLRP3 炎性体激活并通过 TLR4 介导进一步产生 NET
机制。 (3) 将检查来自患有 SLE 的男性和女性的大量数据队列(约 32,000 名)
炎症、免疫疗法和血压的临床标志物之间的关系。提案
使用广泛建立的 SLE 模型、创新的遗传模型、最先进的生理学模型、
药理学和免疫学方法,以及国家人类临床数据数据库
严格测试这些目标。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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MICHAEL RYAN其他文献
MICHAEL RYAN的其他文献
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{{ truncateString('MICHAEL RYAN', 18)}}的其他基金
Renal mechanisms of hypertension in autoimmune disease
自身免疫性疾病中高血压的肾脏机制
- 批准号:
9113934 - 财政年份:2015
- 资助金额:
$ 33.23万 - 项目类别:
Renal mechanisms of hypertension in autoimmune disease
自身免疫性疾病中高血压的肾脏机制
- 批准号:
10436800 - 财政年份:2015
- 资助金额:
$ 33.23万 - 项目类别:
Renal mechanisms of hypertension in autoimmune disease
自身免疫性疾病中高血压的肾脏机制
- 批准号:
9339569 - 财政年份:2015
- 资助金额:
$ 33.23万 - 项目类别:
Mississippi Diversity in Hypertension and Cardiorenal Researchers Program
密西西比州高血压和心肾研究人员多样性计划
- 批准号:
8829330 - 财政年份:2014
- 资助金额:
$ 33.23万 - 项目类别:
Mississippi Diversity in Hypertension and Cardiorenal Researchers Program
密西西比州高血压和心肾研究人员多样性计划
- 批准号:
8616569 - 财政年份:2014
- 资助金额:
$ 33.23万 - 项目类别:
Blood Pressure, Renal Hemodynamics, and Inflammation
血压、肾脏血流动力学和炎症
- 批准号:
7834567 - 财政年份:2009
- 资助金额:
$ 33.23万 - 项目类别:
Blood Pressure, Renal Hemodynamics, and Inflammation
血压、肾脏血流动力学和炎症
- 批准号:
7624984 - 财政年份:2008
- 资助金额:
$ 33.23万 - 项目类别:
Blood Pressure, Renal Hemodynamics, and Inflammation
血压、肾脏血流动力学和炎症
- 批准号:
7800439 - 财政年份:2008
- 资助金额:
$ 33.23万 - 项目类别:
Blood Pressure, Renal Hemodynamics, and Inflammation
血压、肾脏血流动力学和炎症
- 批准号:
7449931 - 财政年份:2008
- 资助金额:
$ 33.23万 - 项目类别:
Blood Pressure, Renal Hemodynamics, and Inflammation
血压、肾脏血流动力学和炎症
- 批准号:
8051642 - 财政年份:2008
- 资助金额:
$ 33.23万 - 项目类别:
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