Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis
Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis
批准号:
10155463
负责人:
Keith L Kirkwood
金额:
$37.88万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-07 至 2023-05-31
关键词:
3&apos Untranslated RegionsAffectAgeAgingAlveolarAlveolar Bone LossAnti-Inflammatory AgentsBindingBloodBone MarrowBone remodelingCell Differentiation processCellsChronicCoinDataDisease ProgressionElderlyElementsFailureFamilyFunctional disorderFutureGene DeliveryHealthHomeostasisHumanImmuneImmune systemImpairmentIncidenceIndividualInflammagingInflammationInflammatoryInflammatory ResponseInterleukin-6Intrinsic factorKnock-in MouseKnockout MiceLinkLymphocyteMaintenanceMatrix MetalloproteinasesMessenger RNAMetabolismMolecularMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsNuclear TranslocationOralOsteoclastsPTGS2 genePathogenicityPerformancePeriodontal DiseasesPeriodontitisPhenotypePopulationPost-Transcriptional RegulationProcessProductionProteinsPublishingRNA-Binding ProteinsRegulationResearch PersonnelResolutionRoleSkeletal boneStreamTIS11 proteinTNF geneTestingTherapeuticTissuesUntranslated Regionsadaptive immunityadenylateage relatedalveolar bonebonebone agingbone losschronic inflammatory diseasecytokinedensitygain of functionhealinghealthy aginginsightlong bonemRNA Stabilitymacrophagemiddle ageoral microbiomeoral pathogenosteoclastogenesispreventprototyperecruitsexskeletalskeletal tissuesmall moleculetherapeutic targeturidylateyoung adult
中文摘要
摘要
随着年龄的增长,免疫系统经历了动态变化,其特征在于免疫功能的损害,
获得性免疫和低度慢性炎症的激活。这种炎症的慢性激活
与衰老或“炎症”有关。Tristetraprolin(TTP)是一种RNA结合蛋白,
与靶mRNA(包括关键的促炎mRNA)的3′-UTR中富含腺苷酸-尿苷酸的元件结合
例如TNFα、考克斯-2和IL-6)促进其快速周转。重要的是,我们最近证明,
不能在转录后水平调节细胞因子的表达导致慢性炎症,
与年龄/性别匹配对照相比,TTP-/-小鼠随年龄的自发牙槽骨丢失。因此,TTP
其表达似乎以年龄依赖性方式对牙槽骨稳态是必需的。我们的初步
本申请中的数据和最近公布的数据强烈支持巨噬细胞和骨髓-
衍生的抑制细胞(MDSC)群体在TTP-/-小鼠中随着年龄的增长而扩增,伴随着减少。
在淋巴细胞群体中。综上所述,我们的研究结果支持了TTP可能是一个关键的内在因素的观点。
炎症因子和髓系扩增/分化,有助于骨骼
体内平衡我们建议检验TTP控制炎症和影响牙槽骨的假设,
长骨骨骼健康随着年龄的增长。该提案的具体目的是:1)明确骨髓来源的作用
TTP对骨稳态随年龄变化的影响; 2)确定TTP用于改变破骨细胞生成的机制
3)确定TTP表达增加是否改变健康衰老期间的骨重塑。在
这些研究的结论,关于TTP的新见解将提供未来的研究,
可能是口腔和非口腔骨骼组织健康老化的治疗靶点。
英文摘要
ABSTRACT
With advancing age, the immune system undergoes dynamic changes characterized by both impairment of
adaptive immunity and activation of low-grade chronic inflammation. This chronic activation of inflammation
associated with aging or `inflammaging'. Tristetraprolin (TTP) is an RNA binding proteins that post-translationally
bind to adenylate-uridylate–rich elements in the 3′-UTR of target mRNAs (including key pro-inflammatory mRNAs
e.g. TNFα, COX-2 and IL-6) to promote their rapid turnover. Importantly, we have recently demonstrated that
failure to regulate expression of cytokines at the posttranscriptional level contributes to chronic inflammation and
spontaneous alveolar bone loss with age in TTP-/- mice compared to age/sex match controls. Thus, TTP
expression appears to be essential for alveolar bone homeostasis in an age-dependent manner. Our preliminary
data in this application and recently published data strongly support the concept that macrophages and myeloid-
derived suppressor cell (MDSC) populations are expanded with age in TTP-/- mice, with concomitant reduction
in lymphocyte populations. Taken together, our results support that notion that TTP may be a critical intrinsic
factor of inflammaging and myeloid lineage expansion/differentiation that contributes towards skeletal
homeostasis. We propose to test the hypothesis that TTP controls inflammaging and impacts alveolar bone and
long bone skeletal health with age. The specific aims of the proposal are: 1) define the role of myeloid-derived
TTP on bone homeostasis with age; 2) determine the mechanisms that TTP uses to alter osteoclastogenesis
with age; and 3) Establish if increased TTP expression alters bone remodeling during healthy aging. At the
conclusion of these studies, new insights regarding TTP will be provided for future studies where would be
potentially a therapeutic target for healthy aging of the oral and non-oral skeletal tissues.
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会议论文
Buffalo Oral-Research and Specialty Training Program (BORST)
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批准号:10658240
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财政年份:2023
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Immunometabolic Regulation of MDSCs in Periodontitis
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批准号:10560308
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Immunometabolic Regulation of MDSCs in Periodontitis
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批准号:10706535
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资助金额:$62.74万
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财政年份:2022
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负责人:Keith L Kirkwood
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依托单位:
Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis
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批准号:10405077
-
项目类别:
-
资助金额:$37.5万
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财政年份:2018
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负责人:Keith L Kirkwood
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依托单位:
Buffalo Oral-Research and Specialty Training Program (BORST)
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批准号:10246196
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项目类别:
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资助金额:$13.27万
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财政年份:2018
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负责人:Keith L Kirkwood
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依托单位:
Buffalo Oral-Research and Specialty Training Program (BORST)
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批准号:10468817
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资助金额:$23.27万
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财政年份:2018
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负责人:Keith L Kirkwood
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Buffalo Oral-Research and Specialty Training Program (BORST)
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批准号:9982900
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项目类别:
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资助金额:$4.84万
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财政年份:2018
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负责人:Keith L Kirkwood
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依托单位:
MUSC Center for Oral Health Research
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批准号:8540443
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项目类别:
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资助金额:$102.13万
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财政年份:2012
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依托单位:
MUSC Center for Oral Health Research
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批准号:8305251
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资助金额:$107.61万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
MUSC Center for Oral Health Research
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批准号:9069886
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项目类别:
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资助金额:$101.61万
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负责人:Keith L Kirkwood
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依托单位:
Administration
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批准号:8466899
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资助金额:$27.62万
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负责人:Keith L Kirkwood
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依托单位:
T-COHR: Summer Undergraduate Research Program
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批准号:8450740
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资助金额:$5.27万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
T-COHR: Summer Undergraduate Research Program
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批准号:8310438
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项目类别:
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资助金额:$5.27万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
MUSC Center for Oral Health Research
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批准号:8921215
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项目类别:
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资助金额:$102.85万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
MUSC Center for Oral Health Research
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批准号:8676547
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资助金额:$103.82万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
T-COHR: Summer Undergraduate Research Program
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批准号:8845538
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资助金额:$5.27万
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财政年份:2012
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负责人:Keith L Kirkwood
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依托单位:
COBRE: MUSC: CORE A: ADMIN
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资助金额:$62.57万
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财政年份:2011
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负责人:Keith L Kirkwood
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Post-Transcriptional Regulation of Periodontal Dise
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资助金额:$0.49万
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财政年份:2011
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资助金额:$36.88万
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依托单位:
海外基金