The role of circadian clock proteins in innate and adaptive immunity
生物钟蛋白在先天性和适应性免疫中的作用
基本信息
- 批准号:10582781
- 负责人:
- 金额:$ 37.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-26 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAgonistAntibody FormationAntigen PresentationAttentionAttenuatedAutonomic nervous systemB cell differentiationB-Cell DevelopmentB-LymphocytesBacteriaBiologicalBiologyBone MarrowCell RespirationCellsCellular biologyClock proteinComplexCuesDataDevelopmentDimensionsDiseaseEvolutionExposure toEyeFRAP1 geneGene ClusterGenesHealthHistocompatibility Antigens Class IIHourHumanHypothalamic structureImmuneImmune responseImmunityImmunocompetenceImmunoglobulinsIn VitroIndividualInfectionInfection ControlInflammationInflammatoryInterferon Type IInterferonsKidneyKlebsiella pneumoniaeLeukocytesLightLiverMammalian CellMediatingMetabolicMitochondriaModelingMolecularMononuclearMusNatural ImmunityNeuraxisOntologyOpticsOrganOrganismOutcomePathway interactionsPatientsPeripheralPhagocytesPhenotypePhysiologicalPhysiologyPineal glandPituitary GlandPneumoniaPopulationProcessProductionProteinsProto-Oncogene Proteins c-aktPublishingReperfusion InjuryResearchRoleSepsisSignal PathwaySignal TransductionSpleenSplenectomyStressSystemTherapeuticTissue DifferentiationTissuesTravelWorkadaptive immunityblue light therapycholinergiccircadiancircadian biologycircadian pacemakerfitnessimmune functionimproved outcomein vivoinnovationmicrobialmonocytemouse modelneurophysiologyorgan injurypathogenprogramsrecruitresponserev Proteinsepticsingle-cell RNA sequencingsuprachiasmatic nucleussystemic inflammatory responsetissue injury
项目摘要
ABSTRACT
Within each mammalian cell is a core set of circadian clock proteins that regulate the cellular biology
supporting more complex organ physiologies. The central nervous system, entrained by the principle
environmental cue – light, synchronizes these peripheral cellular ‘clocks’ across the entire organism, which
enables the host organism to anticipate and prepare for the stresses of the active day (e.g., metabolic
demands, septic threat). The current evidence, including data derived from our own research program,
highlight the profound influence individual clock proteins have on the physiologic capacity with which an
organism responds to stress. We first identified that the spectrum of light is a critical determinant of its effects
on mammalian biology, and that the short wavelength visible blue spectrum favorably modifies the
biology and outcome of sepsis. In murine models of intraabdominal sepsis and Klebsiella pneumoniae (KP)
pneumonia, exposure to blue light after sepsis enhanced immune competence, as evidenced by more efficient
clearance of bacteria from the septic focus, reduced bacterial dissemination, and attenuated systemic
inflammation. The mechanism involved an optic-cholinergic pathway that induced the clock protein Rev-Erba
in immune tissues of the spleen and Mj. A Rev-Erba agonist similarly enhance immune function in both in vitro
and in vivo studies. Our overarching hypothesis is that the cellular state of the clock protein Rev-Erba is
a critical determinant of immune competence and can be modulated to improve the outcome of sepsis.
We specifically hypothesize that Rev-Erba regulates the protein machinery supporting the immune
phenotype of the mononuclear phagocyte and B cell and is vital to an efficient immune response to
microbial threat.
In Aim 1 we will study the physiologic and cellular mechanisms by which blue light and the clock protein
Rev-Erba regulate monocyte recruitment to the spleen and peripheral tissues and differentiation into a type of
monocyte highly efficient in bacterial clearance, using a model of KP pneumonia. In Aim 2, we will explore the
mechanisms by which blue light and Rev-Erba modulate B cell PI3K-AKT-mTOR signaling and actin assembly
to mediate B cell differentiation, activation, MHC II antigen presentation, and antibody production. As these
mechanisms are metabolically demanding and ATP-dependent, we will (Aim 3) determine the mechanisms by
which Rev-Erba modulates mitochondrial dynamics to support oxidative metabolism and thereby the
phenotype of immune cells during sepsis.
The ramifications of light on health and disease remain to be convincingly defined. This proposal will define
the biological mechanisms through which circadian clock proteins beneficially alter the host response to acute
infectious insult. We will define the dimensions of light and state of clock proteins that are optimally protective
and examine their biological relevance and potential therapeutic value in studies of patients with pneumonia.
摘要
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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MATTHEW Randall ROSENGART其他文献
MATTHEW Randall ROSENGART的其他文献
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{{ truncateString('MATTHEW Randall ROSENGART', 18)}}的其他基金
The role of circadian clock proteins in innate and adaptive immunity
生物钟蛋白在先天性和适应性免疫中的作用
- 批准号:
10892546 - 财政年份:2022
- 资助金额:
$ 37.36万 - 项目类别:
Calcium homeostasis and cellular fitness in sepsis
脓毒症中的钙稳态和细胞适应性
- 批准号:
10892600 - 财政年份:2022
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: central regulators of the inflammatory response to surgical sepsis
CaMK:手术败血症炎症反应的中央调节因子
- 批准号:
8516525 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: Central Regulators of the response to Surgical Sepsis
CaMK:手术败血症反应的中央监管者
- 批准号:
9043106 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: Central Regulators of the response to Surgical Sepsis
CaMK:手术败血症反应的中央监管者
- 批准号:
9407788 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: central regulators of the inflammatory response to surgical sepsis
CaMK:手术败血症炎症反应的中央调节因子
- 批准号:
8308620 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: central regulators of the inflammatory response to surgical sepsis
CaMK:手术败血症炎症反应的中央调节因子
- 批准号:
7906839 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
CaMK: central regulators of the inflammatory response to surgical sepsis
CaMK:手术败血症炎症反应的中央调节因子
- 批准号:
8114205 - 财政年份:2009
- 资助金额:
$ 37.36万 - 项目类别:
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