Neutrophil lineage in inflammation
Neutrophil lineage in inflammation
批准号:
10470237
负责人:
Sergio Daniel Catz
金额:
$248.73万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-16 至 2026-05-31
关键词:
AddressAdultApoptosisAreaArterial Fatty StreakAtherosclerosisAttenuatedAutomobile DrivingBiologyBlood CellsBlood CirculationBone MarrowCardiovascular DiseasesCause of DeathCell LineageCell physiologyCellsCellular biologyCessation of lifeChronicComplexCoronary ArteriosclerosisCuesCytoplasmic GranulesDataDevelopmentDiseaseDisease ProgressionEndotheliumEvaluationExocytosisGeneticGoalsGranulopoiesisHeart DiseasesHematological DiseaseHematopoietic stem cellsHeterogeneityHumanHyperlipidemiaImmuneImmunologyInfectionInflammasomeInflammationInflammatoryInterleukin-1Interleukin-1 betaInvadedLaboratory ResearchLesionLongevityMammalsMediatingMediator of activation proteinMissionMitochondriaModelingMolecularMusMyocardial InfarctionNational Heart, Lung, and Blood InstituteNeutrophil ActivationPathogenesisPathogenicityPathologicPathologyPlasmaPreventionProcessProductionProteinsReceptor SignalingRegulationResearch PersonnelResearch Project GrantsRoleRuptureSignal TransductionTechnologyTestingTissuesValidationatherogenesisdesignextracellularhuman subjectinterdisciplinary approachmicroorganismneutrophilnovel strategiesnovel therapeuticspre-clinicalprogenitorprogramsresponsesecretory proteintraffickingtranslational approach
中文摘要
摘要
中性粒细胞构成了细胞防御病原微生物的第一道防线。回应亲王-
炎症提示,不受限制的中性粒细胞激活会导致组织损伤。以避免对人类健康的有害影响
宿主、中性粒细胞数量、激活和寿命必须受到严格控制,但分子机制
在炎症性疾病的背景下控制中性粒细胞仍然难以捉摸。心血管疾病是最主要的
全球死因。最近的证据支持中性粒细胞在冠状动脉病变发展中的重要作用
动脉疾病(CAD)。中性粒细胞存在于早期的主动脉病变和易破裂的动脉粥样硬化中
中性粒细胞分泌蛋白水平与冠心病呈正相关。
证实了这一点,表明中性粒细胞胞吐在冠心病中介导了有害的影响。此外,中性粒细胞
动脉粥样硬化模型和新发现的中性粒细胞前体在骨髓中的产生增加
现在已知可以调节炎症。中性粒细胞亚群在冠心病疾病进展中的作用
目前还没有研究,中性粒细胞多样性在疾病中的调节尚不清楚。炎症室是一种
动脉粥样硬化的新兴驱动因素;然而,NLRP3炎症小体选择性激活在动脉粥样硬化中的作用
中性粒细胞在动脉粥样硬化形成中的作用以及中性粒细胞功能的调控机制尚未见报道
在炎性小体激活和动脉粥样硬化形成的背景下,谱系细胞仍然未知。在这个协同效应中
炎症和动脉粥样硬化期间中性粒细胞的发展将研究中性粒细胞如何
冠心病患者的异质性被调节,以及中性粒细胞中的NLRP3炎性小体是如何
在动脉粥样硬化中,祖细胞影响粒细胞和中性粒细胞的异质性。项目2中性粒细胞
炎症和动脉粥样硬化过程中的机制将检验高脂血症不同的假说
调控冠心病中性粒细胞前体的囊泡转运及相关功能,建立机制
抑制NLRP3诱导的中性粒细胞胞吐失调,并实施翻译方法以减少
冠心病患者的中性粒细胞炎症。项目3炎症状态下中性粒细胞的存活和死亡
中性粒细胞中NLRP3炎性小体成分的表达及功能研究
血统,并将确定高脂血症引起的炎症的影响和死亡受体的作用
IL-1β产生中的信号转导、中性粒细胞存活中线粒体的凋亡和坏死性下垂
动脉粥样硬化形成中的信号转导。我们的协同和独特的计划使用了三个互补的专业知识
中性粒细胞发育、中性粒细胞细胞内功能调节领域的知名研究人员、专家
和炎症,以研究中枢假说,即不受限制地激活中性粒细胞和成熟祖细胞
中性粒细胞是心血管疾病的基本过程。这些研究将带来新的方法来
治疗冠心病中性粒细胞介导性炎症。
英文摘要
ABSTRACT
Neutrophils constitute the first line of cellular defense against pathogenic microorganisms. In response to pro-
inflammatory cues, unrestricted neutrophil activation induces tissue damage. To avoid deleterious effects to the
host, neutrophil numbers, activation, and lifespan must be tightly regulated, but the molecular mechanisms that
control neutrophils in the context of inflammatory disease remain elusive. Cardiovascular disease is the leading
global cause of death. Recent evidence supports an important role for neutrophils in the development of coronary
artery disease (CAD). Neutrophils are present in early aortic lesions and in rupture-prone atherosclerotic
plaques, and a positive correlation between plasma levels of neutrophil secretory proteins and CAD has been
established, suggesting that neutrophil exocytosis mediates detrimental effects in CAD. Furthermore, neutrophil
production is increased in the bone marrow in atherosclerotic models and newly identified neutrophil precursors
are now known to mediate inflammation. How neutrophil subsets contribute to disease progression in CAD has
not been studied and the regulation of neutrophil diversity in disease is unknown. The inflammasome is an
emerging driver in atherosclerosis; however, the role of the NLRP3 inflammasome activation selectively in
neutrophils on atherogenesis has not been studied and the mechanisms regulating the functions of neutrophil
lineage cells in the context of inflammasome activation and atherogenesis remain unknown. In this synergistic
program, Project 1 Neutrophil Development During Inflammation and Atherosclerosis will study how neutrophil
heterogeneity is modulated in human subjects with CAD, and how the NLRP3 inflammasome in neutrophil
progenitors influences granulopoiesis and neutrophil heterogeneity in atherosclerosis. Project 2 Neutrophil
Mechanisms During Inflammation and Atherosclerosis will test the hypothesis that hyperlipidemia differentially
regulates vesicular trafficking and associated functions of neutrophil precursors in CAD, establish mechanisms
of NLRP3-induced neutrophil exocytosis dysregulation and implement translational approaches to decrease
neutrophil inflammation in CAD. Project 3 Neutrophil Survival and Demise During Inflammatory States will
characterize the expression and function of components of the NLRP3 inflammasome in cells of the neutrophil
lineage, and will define the effects of hyperlipidemia-induced inflammation and the roles of death receptor
signaling in IL-1β production, mitochondrial apoptosis in viability of neutrophil lineage cells, and necroptosis
signaling in atherogenesis. Our synergistic and unique program uses the complementary expertise of three
renown researchers, experts in the areas of neutrophil development, neutrophil intracellular function regulation
and inflammation, to study the central hypothesis that unrestricted activation of neutrophil progenitors and mature
neutrophils is a fundamental process in cardiovascular disease. These studies will lead to novel approaches to
treat neutrophil-mediated inflammation in CAD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
2023 Phagocytes Gordon Research Conference and Gordon Research Seminar
-
批准号:10683594
-
项目类别:
-
资助金额:$1.1万
-
财政年份:2023
-
负责人:Sergio Daniel Catz
-
依托单位:
Neutrophil Mechanisms During Inflammation and Atherosclerosis
-
批准号:10270898
-
项目类别:
-
资助金额:$62.25万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Admin Core
-
批准号:10470238
-
项目类别:
-
资助金额:$26.84万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Admin Core
-
批准号:10651780
-
项目类别:
-
资助金额:$26.58万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Admin Core
-
批准号:10270895
-
项目类别:
-
资助金额:$28.39万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Neutrophil lineage in inflammation
-
批准号:10270894
-
项目类别:
-
资助金额:$258.19万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Neutrophil Mechanisms During Inflammation and Atherosclerosis
-
批准号:10470241
-
项目类别:
-
资助金额:$59.5万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Neutrophil Mechanisms During Inflammation and Atherosclerosis
-
批准号:10651790
-
项目类别:
-
资助金额:$58.73万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Neutrophil lineage in inflammation
-
批准号:10651774
-
项目类别:
-
资助金额:$246.46万
-
财政年份:2021
-
负责人:Sergio Daniel Catz
-
依托单位:
Small Molecule inhibitors of late endosomal pro-inflammatory signaling
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批准号:9217039
-
项目类别:
-
资助金额:$42.57万
-
财政年份:2017
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负责人:Sergio Daniel Catz
-
依托单位:
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
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批准号:10801704
-
项目类别:
-
资助金额:$10.77万
-
财政年份:2017
-
负责人:Sergio Daniel Catz
-
依托单位:
Small Molecule inhibitors of late endosomal pro-inflammatory signaling
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批准号:9769522
-
项目类别:
-
资助金额:$42.57万
-
财政年份:2017
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负责人:Sergio Daniel Catz
-
依托单位:
Modulators of granulocyte regulated secretion for control of inflammation
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批准号:8629774
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项目类别:
-
资助金额:$36.01万
-
财政年份:2013
-
负责人:Sergio Daniel Catz
-
依托单位:
Modulators of granulocyte regulated secretion for control of inflammation
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批准号:8480393
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项目类别:
-
资助金额:$36.01万
-
财政年份:2013
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:8703748
-
项目类别:
-
资助金额:$46.43万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:10225236
-
项目类别:
-
资助金额:$43.4万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:10754207
-
项目类别:
-
资助金额:$71.53万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:8578053
-
项目类别:
-
资助金额:$45.1万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:8843523
-
项目类别:
-
资助金额:$46.66万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
-
依托单位:
Vesicular trafficking mechanisms regulating granulocyte function
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批准号:9520929
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项目类别:
-
资助金额:$48.38万
-
财政年份:2008
-
负责人:Sergio Daniel Catz
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依托单位:
海外基金