Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG

EGCG 抑制 CCR1/CCR5 介导的血管生成和关节破坏

基本信息

批准号：
7513319
负责人：
Salah-uddin Ahmed
金额：
$ 7.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7513319
关键词：
Adjuvant Adjuvant Arthritis Adoptive Transfer Animal Model Anti-Inflammatory Agents Anti-inflammatory Arthritis Autoimmune Diseases Bone and Cartilage Funding CCR1 gene Cartilage Cells Chemokine (C-C Motif) Receptor 5 Chemotaxis Chimera organism Chronic Dermal Development Dinoprostone Enzymes Epigallocatechin Gallate Fibroblasts Foundations Gelatinase A Green tea Human Implant Incidence Inflammatory Inhibition of Matrix Metalloproteinases Pathway Interleukin-12 Interleukin-6 Interleukins Invasive Joints Lead Macrophage Inflammatory Proteins Matrix Metalloproteinase Inhibitor Mediating Methods Modeling Mononuclear Nature Onset of illness Production Proteins Rattus Regulation Rheumatoid Arthritis SCID Mice Severe Combined Immunodeficiency Severities Signal Pathway Signal Transduction T-Lymphocyte Testing Therapeutic Tissue Grafts Tissues Treatment Protocols Vascular Endothelial Cell Vascular Endothelial Growth Factors Work analog angiogenesis arthropathies articular cartilage bone chemokine cyclooxygenase 2 disability gallocatechol health economics in vivo macrophage monocyte novel novel therapeutics prevent receptor expression research study success

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which activated synovial fibroblasts produce chemokines that facilitate the invasion of the articular cartilage and underlying bone by the release of matrix-degrading enzymes. Importantly, RANTES/CCL5 and macrophage inflammatory protein (MIP-11)/CCL3 are the chemokines shown to activate CCR1 and CCR5 receptor to attract T cells and monocytes into joints during the onset of disease. Thus, regulation of CCR1/CCR5 receptor expression is emerging as a novel therapeutic strategy for RA. In our preliminary findings, epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory molecule, blocked interleukin-12 (IL-12)-induced RANTES/CCL5 and MIP-11/CCL3 ) production in RA synovial fibroblasts that are mediated via CCR1/CCR5 receptors. EGCG also inhibited IL-12-induced markers of cartilage and bone destruction (IL-6, VEGF, and PGE2), and matrix degrading enzyme matrix metalloproteinase-2 (MMP-2) activity in human RA synovial fibroblasts. [An in vivo study showed that EGCG prevented adjuvant-induced arthritis (AIA) in rats.] This proposal capitalizes on these novel observations. The central hypothesis of the work proposed is that EGCG inhibits cell recruitment, angiogenesis and joint destruction in rat adjuvant-induced arthritis (AIA) model and in RA synovial tissue (ST)-severe combined immunodeficient (SCID) chimera by blocking CCR1/CCR5 receptor expression. In Aim 1, we will test whether EGCG inhibits CCR1/CCR5 receptor expression to suppress RANTES/CCL5 or MIP-11/CCL3 activity and angiogenesis in RA ST explants. In Aim 2, we will study if EGCG blocks CCR1/CCR5 receptor mediated cell recruitment and tissue invasion in a human RA ST- severe combined immunodeficiency (SCID) mouse chimera. Finally, in Aim 3, we will determine whether EGCG downregulates CCR1/CCR5 receptor expression to inhibit angiogenesis, and cartilage and bone destruction in a rat AIA model of RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potential treatment option for RA and possibly other autoimmune diseases. PROJECT NARRATIVE Rheumatoid arthritis (RA), a chronic inflammatory joint disorder, is a leading cause of work-related disabilities and a significant socio-economic health challenge due to expensive, yet incomplete, conventional therapies. Using animal models of human RA, we propose to test the efficacy of epigallocatechin-3-gallate (EGCG), a potential anti-inflammatory molecule found in green tea, in inhibiting the destruction of the cartilage and bone in RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potentially safe and inexpensive treatment option for RA.

描述（由申请人提供）：项目摘要类风湿关节炎（RA）是一种慢性炎症性关节疾病，激活的滑膜成纤维细胞产生趋化因子，可通过释放基质降解酶来促进关节软骨和基础骨的侵袭。重要的是，RANTES/CCL5和巨噬细胞炎症蛋白（MIP-11）/CCL3是显示在疾病发作期间激活CCR1和CCR5受体的趋化因子，以将T细胞和单核细胞吸引到关节中。因此，CCR1/CCR5受体表达的调节正在成为RA的一种新型治疗策略。在我们的初步发现中，epigalocatechin-3-gallate（EGCG），一种有效的抗炎分子，阻断了RA综合成核细胞中介导的ra合成细胞中产生的IL-12（IL-12）诱导的rantes/ccl5和mip-11/ccl3）诱导的rantes/ccl5和mip-11/ccl3通过CCR1/CCR5受体。 EGCG还抑制了软骨和骨破坏的IL-12诱导的标记（IL-6，VEGF和PGE2），以及在人RA synovial synovial成纤维细胞中降解酶基质金属蛋白酶-2（MMP-2）活性的基质降解。 [一项体内研究表明，EGCG可防止辅助性诱导的关节炎（AIA）。提出的工作的中心假设是，EGCG抑制大鼠辅助引起的关节炎（AIA）模型的细胞募集，血管生成和关节破坏，以及RA滑膜组织（ST） - 严重性结合结合的免疫缺陷（SCID）嵌合在表达。在AIM 1中，我们将测试EGCG是否抑制CCR1/CCR5受体表达以抑制RA ST Explants中的Rantes/CCL5或MIP-11/CCL3活性和血管生成。在AIM 2中，我们将研究EGCG是否阻止了人类RA ST-严重合并免疫缺陷（SCID）小鼠嵌合体中CCR1/CCR5受体介导的细胞募集和组织侵袭。最后，在AIM 3中，我们将确定EGCG是否下调了CCR1/CCR5受体表达以抑制RA的大鼠AIA模型中的血管生成以及软骨和骨破坏。提出的实验的成功可能会导致EGCG发展作为RA和可能其他自身免疫性疾病的潜在治疗选择的显着进步。慢性炎症性关节疾病是项目叙述性类风湿关节炎（RA），是与工作有关的残疾的主要原因，并且由于昂贵但不完整的常规疗法而引起的社会经济健康挑战很大。使用人类RA的动物模型，我们建议测试绿茶中发现的潜在的抗炎分子，以抑制RA中的软骨和骨骼的破坏。提出的实验的成功可能会导致EGCG发展作为RA的潜在安全且廉价的治疗选择。