The Role of Inflammation in Cardiovascular Disease
炎症在心血管疾病中的作用
基本信息
- 批准号:9978598
- 负责人:
- 金额:$ 241.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAngiotensin IIAntigen PresentationAtherosclerosisBiological AssayBiologyBlood PressureBlood VesselsCD28 geneCardiovascular DiseasesCatecholaminesCause of DeathCell physiologyCellsCitiesCollaborationsCoronary ArteriosclerosisDendritic CellsDimerizationDiseaseEpigenetic ProcessEventExcess Dietary SaltGenetic TranscriptionGoalsHumanHybridomasHyperlipidemiaHypertensionImmuneImmunityInflammationInflammatoryInterleukin-1 betaInterleukin-6LaboratoriesLeadLesionMaintenanceMajor Histocompatibility ComplexMatrix MetalloproteinasesMeasurementMediatingMemoryMolecularMorbidity - disease rateMusMyelogenousMyeloid-derived suppressor cellsNeuraxisNuclear TranslocationOxidation-ReductionOxidative StressPathologyPathway interactionsPatientsPeptidesPeptidyl-Dipeptidase APhenotypePost-Translational Protein ProcessingProcessProductionProgram Research Project GrantsProteinsProteomeProteomicsPublic HealthPyruvate KinaseReactive Oxygen SpeciesRenal functionResearchResolutionRisk FactorsRoleSignal TransductionSocietiesSodiumStimulusSuppressor-Effector T-LymphocytesSympathetic Nervous SystemT cell responseT memory cellT-Cell ActivationT-Cell ReceptorT-LymphocyteTextUrsidae FamilyWarburg Effectadductcancer cellcytokinedisabilitydisabling diseaseimmunogenicimmunogenicitykidney dysfunctionmacrophagemortalitymouse modelnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsprogramsscreeningsmall molecule
项目摘要
PROJECT SUMMARY
The overall goal of this Program Project Grant is to understand how immune cells including macrophages,
dendritic cells (DCs) and T cells are activated and contribute to cardiovascular diseases including
atherosclerosis and hypertension. The major theme is that common insults including atherogenic risk factors,
catecholamines, oxidative stress, angiotensin II and excessive salt lead to disregulation of immune cells,
leading to local and systemic inflammation. These events promote vascular lesion formation, renal dysfunction,
blood pressure elevation and likely other inflammatory processes, common to humans with cardiovascular
disease. Project 1 will examine how T cells are activated in hypertension, particularly the role of signals from
the central nervous system. Novel mice will be used that allow study of how the sympathetic nervous system
stimulates dendritic cells and ultimately T cells. Drs. Harrison and Bernstein have identified an oxidative protein
modification that promotes DC immunogenicity. An important collaboration will be to identify specific isoketal
adducted peptides in MHC1 that are capable of activating T cells responsible for hypertension. Studies will also
address how memory cells participate in hypertension caused by repeated hypertensive stimuli. Studies with
Project 3 will examine Studies performed with project 2 will examine epigenetic alterations of T cell subtypes in
humans with hypertension. Dr. Cornelia Weyand, the director of project 2 has discovered that macrophages
from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce
excess IL-1β and IL-6. Together with Core A and Dr. Harrison, Dr. Weyand has shown that reactive oxygen
species induce dimerization of PKM2 and its nuclear translocation, where it promotes cytokine production and
feed-forward activation of glycolytic flux; a pathology resembling the Warburg effect of cancer cells. This
project will define factors that modulate the oligomeric state of PKM2, determine how it leads to cytokine
transcription, and examine its role in both atherosclerosis and hypertension. As part of project 2, Dr. Weyand
will seek to examine the efficacy of several promising small molecules to normalize function of macrophages
from humans with atherosclerosis and hypertension. Dr. Bernstein, the director of project 3, brings to bear his
expertise in the biology of the angiotensin I-converting enzyme (ACE). His group will define previously
unrecognized roles of ACE in the initiation, maintenance and resolution of inflammation, by modifying cytokine
production, antigen presentation in MHC-1 and function of myeloid suppressor cells. Through collaboration
with Dr. Markus Kalkum at the City of Hope, Dr. Bernstein will examine how ACE influences the macrophage
proteome and peptidome. All projects make use of Core A, which provides expertise in measurement of
reactive oxygen species. Overall, this program project grant promises to provide new understanding of the
molecular mechanisms of inflammation in cardiovascular diseases and promises to identify new therapeutic
targets to reduce morbidity and mortality in these common and devastating illnesses.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Editorial: Vascular Inflammation in Systemic Autoimmunity.
社论:全身性自身免疫性血管炎症。
- DOI:10.3389/fimmu.2016.00471
- 发表时间:2016
- 期刊:
- 影响因子:7.3
- 作者:Ramirez,GiuseppeA;Weyand,Cornelia;Vaglio,Augusto;Manfredi,AngeloA
- 通讯作者:Manfredi,AngeloA
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David G Harrison其他文献
Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk
IL-1β 抑制对血压、高血压和残余炎症风险的影响
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:8.3
- 作者:
A. Rothman;Jean G Macfadyen;T. Thuren;A. Webb;David G Harrison;T. Guzik;P. Libby;R. Glynn;P. Ridker - 通讯作者:
P. Ridker
Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase during Cell Growth Materials and Methods Cell Culture
细胞生长过程中内皮一氧化氮合酶的转录后调节 材料和方法 细胞培养
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Charles D. Searles;Yoichi Miwa;David G Harrison;S. Ramasamy;D. Searles - 通讯作者:
D. Searles
Isolevuglandins promote autoimmunity and hypertension in systemic lupus erythematosus
异黄兰素促进系统性红斑狼疮的自身免疫和高血压
- DOI:
10.1101/2020.02.10.20021741 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
David M. Patrick;N. Visitación;M. Ormseth;C. M. Stein;Sean S. Davies;Valery N. Yermalitsky;V. Amarnath;Leslie J. Crofford;Jonathan M Williams;S. Dikalov;A. Dikalova;Liang Xiao;Justin P. Van Beusecum;Mingfang Ao;A. Fogo;Kirabo Annet;David G Harrison - 通讯作者:
David G Harrison
88 - The Redox Sensitive Inactivation of Mitochondrial Sirt3, SOD2 Hyperacetylation and Complex I Superoxide Production in Endothelial Dysfunction and Hypertension
- DOI:
10.1016/j.freeradbiomed.2015.10.128 - 发表时间:
2015-10-01 - 期刊:
- 影响因子:
- 作者:
Anna E Dikalova;Hanna A Itani;Rafal R Nazarewicz;William G McMaster;Joshua P Fessel;Jorge L Gamboa;David G Harrison;Sergey Dikalov - 通讯作者:
Sergey Dikalov
REGIONAL VARIATION IN ARTERIAL RESPONSE TO NOREPINEPHRINE DURING FETAL (F) AND NEWBORN (N) LIFE
- DOI:
10.1203/00006450-198704010-00435 - 发表时间:
1987-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Kenneth T Nakamura;Beth M Alden;David G Harrison;Nancy J Rusch;Jean E Robillard - 通讯作者:
Jean E Robillard
David G Harrison的其他文献
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{{ truncateString('David G Harrison', 18)}}的其他基金
Common Inflammation Pathways between Aging and Hypertension That Weaken Bone
衰老和高血压之间削弱骨骼的常见炎症途径
- 批准号:
10430633 - 财政年份:2022
- 资助金额:
$ 241.31万 - 项目类别:
Common Inflammation Pathways between Aging and Hypertension That Weaken Bone
衰老和高血压之间削弱骨骼的常见炎症途径
- 批准号:
10618349 - 财政年份:2022
- 资助金额:
$ 241.31万 - 项目类别:
Vanderbilt Hypertension and Blood Pressure Regulation Program
范德比尔特高血压和血压调节计划
- 批准号:
10385839 - 财政年份:2019
- 资助金额:
$ 241.31万 - 项目类别:
Vanderbilt Hypertension and Blood Pressure Regulation Program
范德比尔特高血压和血压调节计划
- 批准号:
10597621 - 财政年份:2019
- 资助金额:
$ 241.31万 - 项目类别:
Mechanisms of T cell Activation in Hypertension
高血压中 T 细胞激活的机制
- 批准号:
9978625 - 财政年份:2016
- 资助金额:
$ 241.31万 - 项目类别:
The Role of The T Cell In The Genesis of Hypertension
T 细胞在高血压发生中的作用
- 批准号:
9273740 - 财政年份:2015
- 资助金额:
$ 241.31万 - 项目类别:
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