CB2 Receptor Regulatin of Inflammatory Response in EAE

EAE 炎症反应的 CB2 受体调节

• 批准号: 8271463
• 负责人: Doina Ganea
• 金额: $ 5.41万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271463
• 关键词: Address; Adhesions; Affect; Agonist; Allogenic; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Area; Attenuated; Autoimmune Process; Blood Vessels; Brain; C57BL/6 Mouse; CCL19 gene; CCL2 gene; CCL21 gene; CD4 Positive T Lymphocytes; CNR1 gene; CNR2 gene; CXCR3 gene; Cannabinoids; Cannabis; Cannabis sativa plant; Cell Adhesion Molecules; Cells; Cerebral Infarction; Cerebrum; Chronic; Clinical; Coculture Techniques; Country; Data; Dendritic Cells; Development; Disease; Dose; Endogenous Factors; Endothelial Cells; Endothelium; Eragrostis; Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Fluorescence; Goals; Hormones; Immune; Immunization; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integrin alpha4beta1; Intercellular adhesion molecule 1; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-6; Intervention; Label; Leukocyte Rolling; Leukocytes; Ligands; Mediating; Middle Cerebral Artery Occlusion; Modeling; Modification; Molecular; Motor; Multiple Sclerosis; Mus; Myelogenous; Neurodegenerative Disorders; Neurologic; Neuropeptides; Peripheral; Phenotype; Property; Quality of life; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Signal Transduction; Spinal Cord; Spleen; Synapses; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Testing; Tetrahydrocannabinol; Therapeutic Agents; Tissues; Treatment Cost; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Video Microscopy; analog; attenuation; base; cannabinoid receptor; central nervous system demyelinating disorder; chemokine; chemokine receptor; cytokine; disability; economic impact; immune function; improved; in vivo; interleukin-23; intravital microscopy; member; migration; neurotransmission; novel therapeutics; postcapillary venule; prevent; protective effect; receptor; research study; response; therapeutic evaluation; trafficking

Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, is a major cause of neurological disability in Western countries. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. MS is increasingly recognized as an autoimmune neurodegenerative disease triggered by inflammatory attacks of the CNS. We propose to study a newly synthesized molecule (O-1966) that may significantly reduce the contribution of immune cells to CNS damage. O-1966 is a member of the cannabinoid class of molecules. While cannabinoids derived from the plant Cannabis Sativa have been used for thousands of years, their value in the treatment of diseases such as MS has been limited by their psychoactive properties. Presently, it is possible to target the CB2 receptors, primarily expressed on immune cells, which exhibit immunomodulatory functions. O-1966, a selective CB2 agonist, alters immune functions without psychoactive effects. Preliminary results showed that stimulation of CB2 receptors decreases CNS damage in experimental autoimmune encephalomyelitis (EAE). Our preliminary data suggest that the protective action of O-1966 in EAE occurs through effects on inflammation. In this proposal we will investigate the molecular mechanisms by which O-1966 specifically influences the function of immune cells. The proposed studies will be conducted at both molecular/cellular and whole animal level, to allow a better evaluation of the therapeutic potential of O- 1966. We propose that CB2 receptor activation by the selective CB2R agonist O-1966 results in: 1. changes in the phenotype of effector T cells through the induction of regulatory T cells; and 2. inhibition of encephalitogenic T cell traffic to the CNS through a reduction in T cell rolling and adhesion to the vascular CNS endothelium. In Specific Aim 1 we will evaluate the effect of O-1966 in EAE and characterize the CNS infiltrating cells, based on the hypothesis that CB2 activation results in a shift in T cell differentiation from encephalitogenic Th17/Th1 to regulatory T cells. Based on preliminary studies, we propose that the CB2 selective agonist O-1966 affects T cell differentiation through the induction of tolerogenic dendritic cells. This represents a new research area, since the role of cannabinoids on DC differentiation has not been addressed. In Specific Aim 2 we will examine the effects of O-1966 on encephalitogenic Teffector and Treg cell rolling and adhesion to CNS postcapillary venules by intravital microscopy, its effect on the expression of adhesion molecules in Teff/Treg cells and in CNS endothelial cells, and on the expression of chemokines involved in the recruitment of activated T cells to the perivascular space and CNS parenchyma. The identification of molecular/cellular factors and of the mechanisms involved in the anti-inflammatory effect of CB2 receptor ligands will have a significant impact on the understanding and intervention in CNS autoimmune/inflammatory diseases. The ultimate goal of this proposal is the development of new effective therapeutic agents targeted at modification of the inflammatory responses that contribute to MS.

多发性硬化症(MS)是一种慢性中枢神经系统脱髓鞘疾病，是导致 西方国家的神经性残疾。尽管进行了密集和持续的研究工作，但现有的 治疗方案并不能实质上预防组织损伤和临床残疾。多发性硬化日益增多 被认为是一种由中枢神经系统炎症发作引发的自身免疫性神经退行性疾病。我们 建议研究一种新合成的分子(O-1966)，它可能会显著降低 免疫细胞对中枢神经系统的损伤。O-1966是大麻类分子中的一员。而大麻素 从大麻植物中提取出来的大麻已经使用了数千年，它们的治疗价值 像多发性硬化症这样的疾病一直受到其精神活动特性的限制。目前，可以将目标对准 CB2受体，主要表达在免疫细胞上，具有免疫调节功能。O-1966，a 选择性CB2激动剂，改变免疫功能，不影响精神。 初步结果表明，刺激CB2受体可减轻实验性中枢神经系统损伤 自身免疫性脑脊髓炎(EAE)。我们的初步数据表明，O-1966的保护作用 EAE是通过对炎症的影响而发生的。在这项提案中，我们将通过以下方式研究分子机制 O-1966具体影响免疫细胞的功能。建议的研究将在 分子/细胞和整个动物水平，以允许更好地评估O- 1966年。我们认为选择性CB2R激动剂O-1966激活CB2受体的结果如下：1. 通过诱导调节性T细胞改变效应性T细胞的表型； 通过减少T细胞滚动和抑制脑源性T细胞到中枢神经系统的交通 黏附于血管的中枢神经系统内皮细胞。在具体目标1中，我们将评估O-1966在EAE中的效果 并基于CB2激活导致T细胞漂移的假设，对CNS浸润性细胞进行了表征 脑源性Th17/Th1细胞向调节性T细胞分化。根据初步研究，我们 提示CB2选择性激动剂O-1966通过诱导T细胞耐受而影响T细胞分化 树突状细胞。这代表了一个新的研究领域，因为大麻类物质在DC分化中的作用已经 没有被处理过。在特定目标2中，我们将检测O-1966对脑源性T细胞和 活体显微镜观察Treg细胞在中枢神经系统毛细血管后小静脉上的滚动和黏附 黏附分子在Tef/Treg细胞和中枢神经系统内皮细胞中的表达 趋化因子参与活化的T细胞向血管周围间隙和中枢神经系统实质的募集。 分子/细胞因子的鉴定及其抗炎作用机制的研究 CB2受体配体将对中枢神经系统的认识和干预产生重大影响 自身免疫性/炎症性疾病。这一建议的最终目标是发展新的有效的 治疗药物的目标是改变导致MS的炎症反应。