Activation Defects in T Cells of Aged Mice
老年小鼠 T 细胞的激活缺陷
基本信息
- 批准号:8130780
- 负责人:
- 金额:$ 28.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-30 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdoptive TransferAgeAgingAgonistAntigen-Presenting CellsBiochemicalCD44 geneCD8B1 geneCalcium SignalingCell AgingCell physiologyCell surfaceCellsComplexConjugated CarrierCytoskeletal ProteinsCytoskeletonDataDefectDigestionDiseaseDistalElderlyElectrophoresisEnzymesFailureFamilyFunctional disorderGlycoproteinsGlycoside HydrolasesGlycosidesHaptensImmuneImmune responseImmunoblottingImmunotherapyIn VitroInfectionLaboratoriesLeadLectinLinkMalignant NeoplasmsMediatingMembrane GlycoproteinsMessenger RNAMethodsMicrofluidicsModelingMolecularMusNuclearPTPRC genePatternPeptide HydrolasesPeptidesPhosphorylationPolysaccharidesPredispositionProtein phosphatasePublishingResearch PersonnelReverse Transcriptase Polymerase Chain ReactionSeriesSiteSynapsesSystemT cell responseT-Cell ActivationT-LymphocyteTestingTransferaseTransgenic OrganismsVaccinationWorkage relatedagedbasecell agecytokineextracellularfunctional restorationglycosylationglycosyltransferaseimprovedimproved functioningin vivoknowledge basemacromoleculerepairedresearch studyresponsesegregationsenescencesynaptogenesistumortwo-dimensional
项目摘要
DESCRIPTION (provided by applicant): Prior work has suggested a model for age-related T cell failure in which T cells from aged mice show both altered surface glycoprotein patterns and defects in cytoskeleton-dependent relocalization of surface glycoproteins. In addition, OSGE, a protease specific for O-linked glycoproteins including CD43, CD44, and CD45, has been shown to restore function of aged T cells to levels similar to that of T cells of young donors. Three specific aims will address, respectively, (1) altered glycosylation, (2) cytoskeletal defects, and (3) repair of in vivo immune responses. Aim 1 a will use a battery of specific lectins and glycosidases to determine which T cell surface glycoproteins contribute to diminished synapse formation, calcium signals, and cytokine expression in aged T cells. Aim 1b will use 2D electrophoresis and glycan-profiling to identify the T cell surface glycoproteins whose susceptibility to enzymatic digestion parallels the ability of the enzymes to improve T cell function. Aim 1c uses a multiplex RT-PCR approach to develop a listing of age-related changes in mRNAs for glycosides and glycosyl-transferases. Aim 1 d evaluates specific surface glycoproteins, starting with CD44, CD45, CD4, and CDS, for susceptibility to the functionally relevant enzymes. Aim 2 will explore the molecular basis for the failure of aged T cells to move molecules either into the synapse, or into the distal pole complex (DPC) opposite from the site of APC contact. This aim explores two related hypotheses: (a) that T cell activation defects involve a failure to remove inhibitory molecules, including CD43 and protein phosphatases, from the synapse to the DPC, and (b) that the cytoskeletal defect involves altered phosphorylation of proteins in the ERM family. Aim 3 will use two in vivo adoptive transfer systems to see if enzyme-treated T cells from aged donors show improved function in responses to hapten-carrier conjugates and to transplantable tumors. Improved knowledge of the basis for poor T cell function in old age, and the mechanisms by which enzyme exposure corrects these defects, could point to new ways to protect the elderly from cancer and infection, as well as to improvements in vaccination methods for old people.
描述(由申请人提供):先前的工作提出了一个与年龄相关的T细胞衰竭模型,其中老年小鼠的T细胞显示出表面糖蛋白模式的改变和细胞骨架依赖性表面糖蛋白重新定位的缺陷。此外,OSGE是一种针对o -连接糖蛋白(包括CD43、CD44和CD45)的蛋白酶,已被证明可以将老年T细胞的功能恢复到与年轻供者的T细胞相似的水平。三个具体目标将分别解决:(1)糖基化改变,(2)细胞骨架缺陷,(3)体内免疫应答修复。Aim 1a将使用一系列特定的凝集素和糖苷酶来确定哪些T细胞表面糖蛋白有助于减少突触形成、钙信号和衰老T细胞中细胞因子的表达。Aim 1b将使用二维电泳和聚糖谱来鉴定T细胞表面糖蛋白,这些糖蛋白对酶消化的敏感性与酶改善T细胞功能的能力相似。Aim 1c使用多重RT-PCR方法开发糖苷和糖基转移酶mrna的年龄相关变化列表。目的1d评估特异性表面糖蛋白(从CD44、CD45、CD4和CDS开始)对功能相关酶的易感性。Aim 2将探索衰老T细胞无法将分子移动到突触或与APC接触部位相反的远端极复合体(DPC)的分子基础。这一目的探讨了两个相关的假设:(a) T细胞激活缺陷涉及无法去除从突触到DPC的抑制分子,包括CD43和蛋白磷酸酶,以及(b)细胞骨架缺陷涉及ERM家族中蛋白质磷酸化的改变。Aim 3将使用两种体内过继转移系统,观察来自老年供体的经酶处理的T细胞对半抗原载体偶联物和可移植肿瘤的反应是否表现出改善的功能。对老年人T细胞功能低下的基础知识的进一步了解,以及接触酶纠正这些缺陷的机制,可能会指出保护老年人免受癌症和感染的新方法,以及改进老年人的疫苗接种方法。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ex vivo enzymatic treatment of aged CD4 T cells restores antigen-driven CD69 expression and proliferation in mice.
- DOI:10.1016/j.imbio.2010.03.003
- 发表时间:2011-01
- 期刊:
- 影响因子:2.8
- 作者:Garcia, Gonzalo G.;Miller, Richard A.
- 通讯作者:Miller, Richard A.
Antigen-independent expansion of CD28hi CD8 cells from aged mice: cytokine requirements and signal transduction pathways.
老年小鼠 CD28hi CD8 细胞的抗原依赖性扩增:细胞因子需求和信号转导途径。
- DOI:10.1093/gerona/58.12.b1063
- 发表时间:2003
- 期刊:
- 影响因子:0
- 作者:Ortiz-Suárez,Anavelys;Miller,RichardA
- 通讯作者:Miller,RichardA
Age-related defects in the cytoskeleton signaling pathways of CD4 T cells.
- DOI:10.1016/j.arr.2009.11.003
- 发表时间:2011-01
- 期刊:
- 影响因子:13.1
- 作者:Garcia, Gonzalo G.;Miller, Richard A.
- 通讯作者:Miller, Richard A.
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RICHARD A MILLER其他文献
METFORMIN-INDUCED LACTIC ACIDOSIS COMPLICATED BY ACUTE LIVER FAILURE
- DOI:
10.1016/j.chest.2023.07.1294 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:
- 作者:
AMY PAIGE;NOREEN MIRZA;MOHAMMAD RAYAD;RICHARD A MILLER - 通讯作者:
RICHARD A MILLER
PLEURAL EFFUSION-ASSOCIATED DISEASE BURDEN AND COMPLICATIONS IN A PATIENT WITH MALIGNANT MESOTHELIOMA: ANALYSIS FROM NATIONAL INPATIENT SAMPLE
- DOI:
10.1016/j.chest.2024.06.2264 - 发表时间:
2024-10-01 - 期刊:
- 影响因子:
- 作者:
RABIA IQBAL;RUHMA ALI;WAJEEHA AIMAN;RICHARD A MILLER;NIRAV MISTRY - 通讯作者:
NIRAV MISTRY
A CASE REPORT OF SEVERE PULMONARY HYPERTENSION DUE TO IDIOPATHIC PULMONARY FIBROSIS
- DOI:
10.1016/j.chest.2023.07.3944 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:
- 作者:
PRISCILLA CHOW;BARIS VEFALI;WAJEEHA AIMAN;HARI OM SHARMA;SHARATH S BELLARY;ADDI SULEIMAN;RICHARD A MILLER;AMY PAIGE - 通讯作者:
AMY PAIGE
A CASE REPORT OF SEVERE TYPE A AORTIC DISSECTION IN A PATIENT WITH RHEUMATOID ARTHRITIS
- DOI:
10.1016/j.chest.2023.07.1955 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:
- 作者:
PRISCILLA CHOW;BARIS VEFALI;MOHAMMAD ABUSHANAB;RICHARD A MILLER;MARCIN KOCIUBA;AMY PAIGE - 通讯作者:
AMY PAIGE
VENTRICULAR PERFORATION BY STERNOTOMY WIRE IN A DEHISCED STERNAL WOUND OF POST-CABG PATIENT
冠状动脉旁路移植术后胸骨裂开伤口中胸骨切开钢丝导致的心室穿孔
- DOI:
10.1016/j.chest.2023.07.184 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:8.600
- 作者:
MIT CHAUHAN;ASMA JAMIL;RICHARD A MILLER;NAYAAB BAKSHI - 通讯作者:
NAYAAB BAKSHI
RICHARD A MILLER的其他文献
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{{ truncateString('RICHARD A MILLER', 18)}}的其他基金
Integrative Omics to enhance therapeutics development for healthy aging
综合组学促进健康老龄化疗法的开发
- 批准号:
10693877 - 财政年份:2019
- 资助金额:
$ 28.86万 - 项目类别:
Integrative Omics to enhance therapeutics development for healthy aging
综合组学促进健康老龄化疗法的开发
- 批准号:
10475902 - 财政年份:2019
- 资助金额:
$ 28.86万 - 项目类别:
Integrative Omics to enhance therapeutics development for healthy aging
综合组学促进健康老龄化疗法的开发
- 批准号:
10452793 - 财政年份:2019
- 资助金额:
$ 28.86万 - 项目类别:
Integrative Omics to enhance therapeutics development for healthy aging
综合组学促进健康老龄化疗法的开发
- 批准号:
10017120 - 财政年份:2019
- 资助金额:
$ 28.86万 - 项目类别:
Laboratory for Anti-Geric Testing, Evaluation and Research
抗感冒测试、评估与研究实验室
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9899403 - 财政年份:2019
- 资助金额:
$ 28.86万 - 项目类别:
GENETIC ANALYSIS OF STRESS RESISITANCE /LOSS OF HEARING
抗应激/听力损失的遗传分析
- 批准号:
6966784 - 财政年份:2005
- 资助金额:
$ 28.86万 - 项目类别:
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