CB2 Receptor Regulatin of Inflammatory Response in EAE

EAE 炎症反应的 CB2 受体调节

基本信息

批准号：
7715056
负责人：
Doina Ganea
金额：
$ 37.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
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/7715056
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 CD4 Positive T Lymphocytes CNR1 gene CNR2 gene CXCR3 gene Cannabinoids Cannabis Cannabis sativa plant Cell Adhesion Molecules Cell Differentiation process Cells Cerebral Infarction Cerebrum Chronic Clinical Coculture Techniques Country Data Dendritic Cells Development Disease Dose Encephalomyelitis 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 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 Reporting Research Role Signal Transduction Spinal Cord Spleen Synapses 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 intravital microscopy member migration neurotransmission novel therapeutics postcapillary venule prevent protective effect public health relevance receptor research study response therapeutic evaluation trafficking

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Multiple sclerosis, the most common chronic demyelinating disease of the central nervous system, is a major cause of disability in Western countries. Approximately 2.5 million people worldwide and 400,000 Americans suffer from MS. In addition to the often devastating consequences for quality of life for individuals suffering from MS, the economic impact at both the personal and national level is substantial. It is estimated that the annual costs for the treatment of MS is in excess of $2.5 billion. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the current proposal is the development of new effective therapeutic agents for the treatment of MS.

描述（由申请人提供）：多发性硬化症（MS）是一种慢性脱髓鞘疾病的中枢神经系统，是西方国家神经残疾的主要原因。尽管进行了大量和持续的研究工作，但现有的治疗方案并不能实质性地阻止组织损害和临床残疾。 MS越来越被认为是由中枢神经系统发炎攻击触发的自身免疫性神经退行性疾病。我们建议研究新合成的分子（O-1966），该分子可能会显着降低免疫细胞对CNS损伤的贡献。 O-1966是大麻素分子类的成员。尽管源自植物大麻sativa的大麻素已经使用了数千年，但它们在治疗MS等疾病的价值受到其精神活性的限制。目前，可以靶向主要在具有免疫调节功能的免疫细胞上表达的CB2受体。 O-1966是一种选择性CB2激动剂，会改变免疫功能而没有精神活性作用。初步结果表明，CB2受体的刺激减少了实验性自身免疫性脑脊髓炎（EAE）中的中枢神经系统损伤。我们的初步数据表明，O-1966在EAE中的保护作用是通过对炎症的影响而发生的。在此提案中，我们将研究O-1966特异性影响免疫细胞功能的分子机制。拟议的研究将在分子/细胞和整个动物水平上进行，以更好地评估O-1966的治疗潜力。我们提出，选择性CB2受体的激活CB2受体O-1966在：1中导致：1。效应T细胞的变化通过调节性T细胞的诱导效应T细胞的变化；和2。通过减少T细胞滚动和对血管内皮细胞的粘附，抑制脑源性T细胞对CNS的抑制作用。在特定目标1中，我们将根据以下假设来评估O-1966在EAE中的效果，并表征CNS浸润细胞的影响：CB2激活导致T细胞从脑源性TH17/TH1转换为调节T细胞的T细胞分化的变化。基于初步研究，我们建议CB2选择性激动剂O-1966通过诱导耐受性树突状细胞影响T细胞分化。这代表了一个新的研究领域，因为尚未解决大麻素在DC分化中的作用。在特定目标2中，我们将检查O-1966对脑生成tefetor和Treg细胞滚动以及通过内部显微镜对CNS后毛细血管静脉的粘附以及其对TEFF/TREG细胞和CNS内皮细胞中涉及的菌丝菌群中菌落中的菌落细胞中的粘附分子表达的影响，以及在CNS的表达中的影响。实质。 CB2受体配体抗炎作用所涉及的分子/细胞因子的鉴定将对CNS自身免疫/炎症性疾病的理解和干预产生重大影响。该提案的最终目标是开发针对改变有助于MS的炎症反应的新有效治疗剂。公共卫生相关性：多发性硬化症是中枢神经系统中最常见的慢性脱髓鞘疾病，是西方国家残疾的主要原因。全球约有250万人，有40万美国人患有MS。除了对患有MS的人的生活质量往往造成毁灭性后果外，个人和国家一级的经济影响也很大。据估计，MS治疗的年度费用超过25亿美元。尽管进行了大量和持续的研究工作，但现有的治疗方案并不能实质性地阻止组织损害和临床残疾。当前提案的最终目标是开发用于治疗MS的新有效治疗剂。