IL-2 Suppression by Endocannabinoid Activation of PPARgamma

内源性大麻素激活 PPARgamma 抑制 IL-2

基本信息

批准号：
7254283
负责人：
Norbert E Kaminski
金额：
$ 29.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254283
关键词：
2-arachidonylglycerol 9-deoxy-delta-9-prostaglandin D2 Agonist Attenuated Binding Biological Calcium Cell physiology Cells Coxibs Cultured Cells DNA Binding Data Disruption Elevation Endocannabinoids Enzymes Event Exhibits Functional disorder Gene Expression Goals Homeostasis IL2 gene Immune system Immunologics Interleukin-2 Investigation Kinetics Knockout Mice Leukocytes Ligands Maintenance Mediating Metabolism Molecular NF-AT Nuclear Nuclear Receptors Nuclear Translocation Numbers Other Finding PPAR gamma Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Play Preparation Principal Investigator Prostaglandin-Endoperoxide Synthase Prostaglandins Regulation Research Role Series Signal Transduction Small Interfering RNA Staging System T cell regulation T-Cell Activation T-Lymphocyte Testing anandamide arachidonate attenuation base cannabinoid receptor cyclooxygenase 1 cyclooxygenase 2 insight novel nuclear factors of activated T-cells programs protein protein interaction

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this 5 year research plan is to elucidate the molecular mechanism responsible for the modulation of T cell function and interleukin-2 (IL-2) deregulation by the structurally-related endocannabinoids, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). Presently, the teleological role of the endocannabinoid system is unknown but there is a growing body of evidence suggesting that it may significantly contribute to the maintenance of immunologic homeostasis. Numerous studies have demonstrated profound effects on biological systems by AEA and 2-AG, with the immune system representing one of the most extensively characterized. The significance of the current proposed studies is that they will provide direct mechanistic insight into the molecular mechanism by which endocannabinoids modulate T cell function, specifically IL-2 regulation. Novel preliminary results are presented demonstrating that IL-2 suppression by both AEA and 2-AG are dependent on COX-2 metabolism leading to the activation of the nuclear receptor, peroxisome proliferator activated receptor gamma (PPARgamma), independently of CB1 and CB2. Additional results are present suggesting that the specific mechanism involves the disruption of the nuclear factor of activated T cells (NFAT) by PPARgamma activation. Based on the observations described above and other preliminary data presented in the proposal, our present investigation will test the hypothesis: Suppression of IL-2 by the endocannabinoids, AEA and 2-AG, is mediated through disruption of NFAT regulation by two distinct cannabinoid receptor-independent mechanisms: (a) altered intracellular calcium regulation; and (b) activation of PPARgamma following COX-2-mediated conversion of AEA and 2-AG into PPARgamma agonists. We will test our hypothesis using the following specific aims (SA): SA1 is to characterize the role altered intracellular calcium regulation by AEA and 2-AG plays in deregulation of NFAT and, consequently, suppression of IL-2 gene expression; SA2 is to characterize the role of COX-2 on the deregulation of NFAT and suppression of IL-2 by AEA and 2-AG; SA3 is to characterize the role of PPARgamma activation by AEA and 2-AG treatment in altered NFAT regulation and suppression of IL-2; and SA4 is to identify and characterize the bioactive forms of AEA and 2-AG responsible for PPARgamma activation and to elucidate its contribution to IL- 2 suppression.

描述（由申请人提供）：该5年研究计划的总体目标是阐明负责调节T细胞功能和白介素-2（IL-2）的分子机制，结构相关的内源于anandamiDes（AEA）（AEA）（AEA）（AEA））和2-芳烃甘油（2-ag）。目前，内源性大麻素系统的目的论作用尚不清楚，但是越来越多的证据表明，它可能会显着促进免疫稳态的维持。大量研究表明，AEA和2-AG对生物系统的影响很大，其免疫系统代表了最广泛的特征之一。当前提出的研究的意义在于，它们将直接对内源性大麻素调节T细胞功能，特别是IL-2调节的分子机制提供直接的机械洞察力。提出了新的初步结果，表明AEA和2AG抑制IL-2抑制取决于COX-2代谢导致核受体的激活，过氧化物酶体增殖物激活受体伽马（PPARGAMMA），独立于CB1和CB2。还有其他结果表明，特定机制涉及通过PPARGAMMA激活破坏活化T细胞（NFAT）的核因子。基于上述观察结果和提案中提出的其他初步数据，我们目前的研究将检验假设：内源性大麻素，AEA和2-AG抑制IL-2，通过两个不同的大麻素受体对NFAT调节进行介导 - 非依赖性机制：（a）细胞内钙调节的改变；（b）COX-2介导的AEA和2-AG转化为Ppargamma激动剂后的PPARGAMMA的激活。我们将使用以下特定目的（SA）：SA1来检验我们的假设，以表征通过AEA通过AEA和2Ag扮演NFAT的调节而改变的作用，从而改变NFAT的调节，从而抑制IL-2基因表达。 SA2是为了表征Cox-2在NFAT放松管制和通过AEA和2-AG抑制IL-2的作用； SA3是为了表征通过AEA激活PPARGAMMA在NFAT调控和抑制IL-2中激活的作用； SA4旨在识别和表征AEA的生物活性形式和负责PPARGAMMA激活的2-Ag，并阐明其对IL-2抑制的贡献。