PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
基本信息
- 批准号:10282751
- 负责人:
- 金额:$ 13.8万
- 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:2021-07-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAdultAffectAllergic inflammationAmericanAngiotensin IIAnti-Inflammatory AgentsAntigen PresentationAntigensAortaArachidonic AcidsAwardBiological AvailabilityBlood PressureCardiovascular DiseasesCardiovascular systemCell physiologyCellsCyclooxygenase InhibitorsDataDendritic CellsDevelopmentDevelopment PlansDiseaseDisease ProgressionDisease modelEnvironmentEnzymesEpoprostenolEtiologyExperimental ModelsFDA approvedFoundationsGene Expression ProfileHumanHypertensionImmuneImmune responseImmune systemImpairmentIndividualInflammationInflammatoryInflammatory ResponseInfusion proceduresInvadedJournalsKidneyKnockout MiceLaboratoriesLeadLipidsMentorsMetabolic PathwayModelingMorbidity - disease rateMusOrganPTGS2 genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhasePhenotypePlayProductionPropertyProstaglandin ReceptorProstaglandinsPublicationsPulmonary HypertensionRegulatory T-LymphocyteResearchResearch PersonnelRoleSignal PathwaySignal TransductionSiteStimulusT-LymphocyteT-Lymphocyte SubsetsTestingTh1 CellsTh2 CellsTherapeuticThromboxanesTrainingTreprostinilTumor-infiltrating immune cellsUnited StatesVascular DiseasesVasoconstrictor AgentsWild Type Mouseanalogblood pressure regulationcareercareer developmentcell typeclinical investigationclinically significantcyclooxygenase 2cytokineeicosanoid metabolismhigh salt diethypertension controlhypertension treatmentimmune functionimmunoregulationinhibitor/antagonistkidney vascular structuremacrophagemonocytemortalitymouse modelnormotensivenovelnovel therapeuticspreventprogramsreceptorresponsetranscriptome sequencingvascular inflammation
项目摘要
PROJECT SUMMARY
Hypertension is a disease defined as blood pressure that is greater than 130/80mmHg. Hypertension
contributes significantly to cardiovascular disease morbidity and mortality. While the importance of blood
pressure control has become abundantly clear, we are still far from understanding the true etiology of
hypertension. In recent years, inflammation was determined to play a causal role in hypertension. Specifically,
immune cells invade target organs during the course of the disease and release cytokines that cause end-
organ damage. Several studies have determined antigen presentation by dendritic cells (DCs) and monocytes
is important for initiation of hypertension. In addition, pro-inflammatory T cells perpetuate the disease. Anti-
inflammatory T regulatory cells (Treg) can control the hypertensive response. Interestingly, evidence suggests
that long-lasting use of cyclooxygenase inhibitors, which prevent metabolism of arachidonic acid (AA) to
prostaglandins and thromboxane, increases blood pressure. Prostaglandin I2 (PGI2) is an AA metabolite that
our laboratory has determined has immunomodulatory effects. Our group has demonstrated that PGI2 acts to
directly inhibit the functionality of pro-inflammatory DCs and CD4+ Th1 and Th2 cells, while promoting the
function of tolerogenic DCs. However, the impact of PGI2 on the functionality of immune cells in hypertension is
unknown. A previous study has demonstrated that mice deficient in the receptor for PGI2, IP, develop elevated
blood pressure in response to high salt diet, suggesting that PGI2 signaling is important for controlling blood
pressure elevation in response to stimuli. Further, I have preliminary data which suggests that PGI2 controls
the inflammatory response to hypertensive stimuli. Specifically, mice deficient in IP have increased infiltration
of T cells into their aortas compared to wild-type (WT) mice in response to angiotensin II (Ang II). In addition,
infusion of the PGI2 analog treprostinil during the course of Ang II infusion prevents the infiltration of T cells,
monocytes/macrophages and DCs into the aorta of WT mice compared to WT mice that received Ang II and
the vehicle for treprostinil. Thus, these recent studies and my preliminary data lead me to hypothesize
that PGI2 promotes anti-inflammatory responses during hypertension. To test this hypothesis we will use
mouse models of hypertension and primary cells from normotensive and hypertensive mice and humans to:
Aim 1 (K99): Test the hypothesis that PGI2 promotes Treg function and stability during hypertension,
thereby counteracting pro-inflammatory subsets of T cells; and Aim 2 (R00): Test the hypothesis that
PGI2 restrains pro-inflammatory DC and promotes tolerogenic DC function during hypertension.
Determining the mechanisms by which PGI2 controls the immune response to hypertension will greatly
advance the field and result in new therapeutic directions for the treatment of hypertension. These proposed
studies, along with my proposed career development plan, will provide a foundation for my career as an
independent investigator in an outstanding environment.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Allison Elizabeth Norlander其他文献
Allison Elizabeth Norlander的其他文献
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{{ truncateString('Allison Elizabeth Norlander', 18)}}的其他基金
PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
- 批准号:
10731402 - 财政年份:2023
- 资助金额:
$ 13.8万 - 项目类别:
PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
- 批准号:
10447208 - 财政年份:2021
- 资助金额:
$ 13.8万 - 项目类别:
The Effect of Salt on T Cell Function in Hypertension
盐对高血压患者 T 细胞功能的影响
- 批准号:
9138616 - 财政年份:2015
- 资助金额:
$ 13.8万 - 项目类别:
The Effect of Salt on T Cell Function in Hypertension
盐对高血压患者 T 细胞功能的影响
- 批准号:
8908297 - 财政年份:2015
- 资助金额:
$ 13.8万 - 项目类别:
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