Regulation of T Cell Responses in Atherosclerosis
动脉粥样硬化中 T 细胞反应的调节
基本信息
- 批准号:8291596
- 负责人:
- 金额:$ 42.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-02-12 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive TransferAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntigen PresentationArterial Fatty StreakArteriesAtherosclerosisAutoantigensAutoimmune DiseasesAutomobile DrivingBiologicalBlood VesselsCD4 Positive T LymphocytesCardiovascular DiseasesCellsCessation of lifeCholesterolChronicClinicalDataDefectDendritic Cell TherapyDendritic CellsDepositionDevelopmentDiseaseEnhancing LesionEragrostisEventGeneticGrowthHelper-Inducer T-LymphocyteHumanImmune responseImmunityImmunotherapeutic agentIn VitroInflammationInflammatoryInterleukin-1Interleukin-18LaboratoriesLesionLipoproteinsMediatingMethodsMorbidity - disease rateMouse StrainsMusMyeloid CellsPathway interactionsPhenotypePhysiologicalPlayProcessPublishingRecruitment ActivityRegulationRegulator GenesRegulatory T-LymphocyteRoleRuptureSignal TransductionSirolimusSmooth Muscle MyocytesSystemT cell regulationT cell responseT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTestingTo autoantigenUp-RegulationVascular Endothelial CellWorkartery occlusionatheroprotectivebasecell typeclinically relevanthuman FRAP1 proteinhypercholesterolemiain vivomTOR inhibitionmacrophagemevalonatemicroorganism antigenmonocytemortalityperipheral toleranceresearch studyresponsetranscription factortumor
项目摘要
DESCRIPTION (provided by applicant): Compelling evidence supports the hypothesis that inflammation contributes significantly to the development of atherosclerotic lesions and to the catastrophic clinical events associated with unstable lesions. Ample evidence from both human and mouse studies indicate that T lymphocytes play important roles in driving inflammation in atherosclerotic disease. Studies from our laboratory have shown that physiologic mechanisms of regulation of T cell immunity, including modulation of helper T cell subset differentiation, co-stimulatory/co-inhibitory pathways, and regulatory T cells, all significantly impact pro-atherogenic T cell responses. Furthermore, we have established that statins suppress inflammatory effector T cell responses through up-regulation of the transcription factor KLF2. These finding serve as the basis for the proposed project, with the broad objective of discovering ways to therapeutically alter or block the pathogenic T cell responses in arteries. This objective will be pursued through experiments with both mouse and human dendritic cells, macrophages and T cells, both in vitro and in vivo. The work will be organized into the following three interrelated Specific Aims: 1- Develop methods of tolerizing proatherogenic T cells based on induction of KLF2 in dendritic cells. 2- Develop approaches to sustain regulatory T cell (Treg) responses in atherosclerotic lesions under conditions of prolonged hypercholesterolemia. 3- Determine the cellular basis of PD-1 mediated suppression of proatherogenic immune responses. Several experimental approaches will be taken including: pharmacologic manipulation and adoptive transfer of dendritic cells between atherosclerotic-prone mouse strains; lineage specific cre-lox mediated deletion of regulatory genes including KLF2 in DCs and PD-1 in T cells and myeloid cells, all in atherosclerotic-prone mince; and analyses of the effects of cholesterol-induced innate inflammation on Treg viability and phenotype. The work proposed in each Aim address a different basic mechanism of the regulation of T cells in atherosclerotic disease that we know is relevant from our previous work. Each of these mechanisms will likely impact the others, and we will study these interactions. Overall, the information obtained will be of direct translational relevance to the development of immunotherapeutic approaches for cardiovascular disease.
PUBLIC HEALTH RELEVANCE: Atherosclerosis, a leading cause of morbidity and mortality worldwide, is a chronic inflammatory disease of the arterial wall driven in part by T lymphocyte responses. This project will characterize how proatherogenic T lymphocytes are regulated through the interaction with other cells. If successful, the data generated will help in development of new anti-inflammatory treatments for atherosclerosis.
描述(由申请人提供):令人信服的证据支持炎症显著促进动脉粥样硬化病变的发展和与不稳定病变相关的灾难性临床事件的假设。来自人类和小鼠的大量证据表明,T淋巴细胞在动脉粥样硬化疾病的炎症驱动中发挥重要作用。我们实验室的研究表明,T细胞免疫调节的生理机制,包括辅助性T细胞亚群分化的调节、共刺激/共抑制途径和调节性T细胞,都显著影响促粥样硬化T细胞反应。此外,我们已经确定他汀类药物通过上调转录因子KLF2抑制炎症效应T细胞反应。这些发现是该项目的基础,其广泛目标是发现治疗改变或阻断动脉中致病性T细胞反应的方法。这一目标将通过小鼠和人类树突状细胞、巨噬细胞和T细胞的体外和体内实验来实现。这项工作将分为以下三个相互关联的具体目标:1-基于诱导树突状细胞中KLF2的基础上,开发耐受促粥样硬化T细胞的方法。2-在长期高胆固醇血症的情况下,开发维持动脉粥样硬化病变中调节性T细胞(Treg)反应的方法。确定PD-1介导的致动脉粥样硬化免疫反应抑制的细胞基础。几种实验方法将包括:药物操作和树突状细胞在动脉粥样硬化易感性小鼠品系之间的过继转移;谱系特异性cre-lox介导的调控基因缺失,包括dc中的KLF2和T细胞和骨髓细胞中的PD-1,均在动脉粥样硬化易发肉糜中;并分析胆固醇诱导的先天炎症对Treg活力和表型的影响。每个Aim中提出的工作都解决了动脉粥样硬化疾病中T细胞调节的不同基本机制,我们知道这与我们以前的工作相关。这些机制中的每一个都可能影响其他机制,我们将研究这些相互作用。总的来说,获得的信息将与心血管疾病免疫治疗方法的发展直接相关。
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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ANDREW H LICHTMAN其他文献
ANDREW H LICHTMAN的其他文献
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{{ truncateString('ANDREW H LICHTMAN', 18)}}的其他基金
FOCIS Educational Courses: Basic Immunology in Medicine Update, Interventional Im
FOCIS 教育课程:医学基础免疫学更新、介入治疗
- 批准号:
8790941 - 财政年份:2011
- 资助金额:
$ 42.03万 - 项目类别:
FOCIS Educational Courses: Basic Immunology in Medicine Update, Interventional Im
FOCIS 教育课程:医学基础免疫学更新、介入治疗
- 批准号:
8602820 - 财政年份:2011
- 资助金额:
$ 42.03万 - 项目类别:
FOCIS Educational Courses: Basic Immunology in Medicine Update, Interventional Im
FOCIS 教育课程:医学基础免疫学更新、介入治疗
- 批准号:
8213549 - 财政年份:2011
- 资助金额:
$ 42.03万 - 项目类别:
FOCIS Educational Courses: Basic Immunology in Medicine Update, Interventional Im
FOCIS 教育课程:医学基础免疫学更新、介入治疗
- 批准号:
8423788 - 财政年份:2011
- 资助金额:
$ 42.03万 - 项目类别:
FOCIS Educational Courses: Basic Immunology in Medicine Update, Interventional Im
FOCIS 教育课程:医学基础免疫学更新、介入治疗
- 批准号:
8062958 - 财政年份:2011
- 资助金额:
$ 42.03万 - 项目类别:
Endothelial Regulation of T Cell Subset Migration
T 细胞亚群迁移的内皮调节
- 批准号:
7753044 - 财政年份:2009
- 资助金额:
$ 42.03万 - 项目类别:
Regulation of T Cell Responses in Atherosclerosis
动脉粥样硬化中 T 细胞反应的调节
- 批准号:
8452083 - 财政年份:2007
- 资助金额:
$ 42.03万 - 项目类别:
Regulation of T Cell Responses in Atherosclerosis
动脉粥样硬化中 T 细胞反应的调节
- 批准号:
8816114 - 财政年份:2007
- 资助金额:
$ 42.03万 - 项目类别:
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