The reduction of NLRX1 and its role in pulmonary aging
NLRX1的减少及其在肺衰老中的作用
基本信息
- 批准号:9157157
- 负责人:
- 金额:$ 34.34万
- 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:2016-08-15 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Promyelocytic LeukemiaAdenovirus VectorAdultAffectAgeAgingAging-Related ProcessAlveolarAmericasAntiviral AgentsAttenuatedBindingBiological AgingBiological Response ModifiersCell AgingCharacteristicsChronic DiseaseChronic Obstructive Airway DiseaseCytoprotectionDeteriorationDoxycyclineElderlyEventFunctional disorderGene ProteinsGenesGenetic MedicineHealth Care CostsHomeostasisHumanInterventionLeadLeucine-Rich RepeatLoxP-flanked alleleLungMediatingMedicineMitochondriaMolecularMolecular GeneticsMusMutant Strains MiceMutateNucleotidesOralOrganPTEN genePathogenesisPathway interactionsPeripheral Blood Mononuclear CellPhosphotransferasesPhysiologicalPlant RootsPlayPopulationProductionProteinsPulmonary EmphysemaQuality ControlQuality of lifeRisk FactorsRoleSignal TransductionSignaling MoleculeSiteSocietiesStagingSystemTP53 geneTestingTherapeuticTimeTissuesTransgenesTransgenic OrganismsVascular Endothelial Growth Factorsage relatedaging populationcell typedisabilityfunctional declinein vivomacrophagemitochondrial dysfunctionnormal agingnovelnovel strategiesnull mutationoverexpressionrecombinaserestoration
项目摘要
PROJECT SUMMARY
Biological aging of the pulmonary system is associated with structural changes that lead to a progressive
decline in function, and the term “aging lung” is used to describe the organ in this stage of decline. With
population rapidly aging, a thorough understanding of physiologic aging-related changes in the lung is
imperative. We recently demonstrated a mitochondrial molecule, nucleotide-binding domain and leucine-rich-
repeat-containing protein X1 (NLRX1) which has been identified as a negative regulator of mitochondrial
antiviral signaling molecule (MAVS), plays a critical role in the pathogenesis of chronic obstructive pulmonary
disease (COPD). Because aging is a common risk factor for COPD, studies were undertaken to determine if
NLRX1 is an important player in “aging lung.” Our preliminary studies revealed that (i) aging itself induced the
reduction of NLRX1 at the level of gene and protein in murine lungs; (ii) the site of major reduction was in
macrophages; and (iii) the lungs from 12-month-old (mo) NLRX1 null mutant (-/-) mice manifested enhanced
characteristics of the “aging lung.” These features observed from NLRX1-/- mice included (a) activation of the
inflammasome, (b) increased p53 signaling and its target molecule promyelocytic leukemia (PML; a well-known
marker of cellular senescence), (c) decreased production of vascular endothelial growth factor (VEGF), a key
regulator of pulmonary vasculature and cytoprotection and (d) enhancement of senile emphysema-like alveolar
remodeling, all of which were modestly observed in lungs from wild type (WT) controls. In addition, we
identified an unprecedented function of NLRX1 as an interacting molecule with PTEN-induced kinase 1
(PINK1), an essential regulator of mitochondrial quality control. The importance of NLRX1 in aging studies was
evident in humans, revealing the expression of NLRX1 was significantly reduced in peripheral blood
mononuclear cells from the elderly (age>65) compared to those from young controls (age<40). This
constellation of findings led us to hypothesize that aging-induced reduction of NLRX1 plays a critical role
in the aging of pulmonary system via, at least, mitochondrial dysfunction/molecular dysregulation. To
test the hypothesis, we will utilize newly generated mice in which the NLRX1 gene can be null mutated or
induced, respectively, in a temporospatial manner. Proposed aims driven by specific hypotheses are: Aim #1.
Define the alteration of NLRX1 and its role(s) in pulmonary aging in vivo; Aim #2. Determine if restoring the
expression of NLRX1 in vivo attenuates aging-related alterations in the pulmonary system; Aim #3.
Characterize the mitochondrial dysfunction/molecular dysregulation in the lung with aging and define the role
that NLRX1 plays in aging-related mitochondrial dysfunction/molecular dysregulation. To our best knowledge,
NLRX1, an innate immune regulator, has never been studied in the context of aging. Its specific function(s) in
macrophages, in spite of the importance of this cell type for tissue homeostasis with normal aging, have never
been defined, either. The proposed aims will explore these unprecedented issues.
项目总结
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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Min-Jong Kang其他文献
Min-Jong Kang的其他文献
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{{ truncateString('Min-Jong Kang', 18)}}的其他基金
The reduction of NLRX1 and its role in pulmonary aging
NLRX1的减少及其在肺衰老中的作用
- 批准号:
9324115 - 财政年份:2016
- 资助金额:
$ 34.34万 - 项目类别:
Role of NLRX1 in cigarette smoke-induced pulmonary inflammation and remodeling
NLRX1 在香烟烟雾诱导的肺部炎症和重塑中的作用
- 批准号:
9175689 - 财政年份:2016
- 资助金额:
$ 34.34万 - 项目类别:
NLRX1 and MAVS in cigarette smoke-induced inflammation and alveolar remodeling
NLRX1 和 MAVS 在香烟烟雾诱发的炎症和肺泡重塑中的作用
- 批准号:
8916210 - 财政年份:2014
- 资助金额:
$ 34.34万 - 项目类别:
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