Role of NOD2 in Inflammatory Arthritis and Innate Immunity

NOD2 在炎症性关节炎和先天免疫中的作用

• 批准号: 8258632
• 负责人: MICHAEL Patrick DAVEY
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258632
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Acute suppurative arthritis due to bacteria; Address; Agonist; Agreement; Amino Acids; Animal Model; Antibodies; Arterial Fatty Streak; Arthritis; Asthma; Autoantigens; Autoimmunity; B-Lymphocytes; Bacteria; Binding; Biochemical; C-terminal; Caspase; Cell Wall; Cells; Characteristics; Chronic; Colitis; Colorectal Cancer; Complex; Conflict (Psychology); Coronary Arteriosclerosis; Coronary artery; Crohn' s disease; Data; Dermatitis; Development; Disease; Disease Clusterings; Double-Stranded RNA; Eczema; Epitopes; Etiology; Exposure to; Eye; Family; Family member; Flagellin; Funding; Genetic; Gram-Positive Bacteria; Granulomatous; Health; Healthcare; Histopathology; Homeostasis; Host Defense; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunologic Receptors; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Insurance Claim Review; Interleukin-1; Intra-Articular Injections; Invaded; Investigation; Joints; Knockout Mice; Lesion; Leucine-Rich Repeat; Life; Ligands; Link; Lipopolysaccharides; Lipoproteins; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mononuclear; Mus; Mutation; N-terminal; Natural Immunity; Nature; Nucleic Acids; Nucleotides; Onset of illness; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Peptidoglycan; Peripheral; Physiological; Play; Poly C; Poly I-C; Principal Investigator; Process; Production; Proteins; Proteoglycan; Proteomics; RNA; Receptor Activation; Receptor Cross-Talk; Recurrence; Regulation; Regulatory Pathway; Reporting; Rheumatoid Arthritis; Role; Sarcoidosis; Septic Shock; Site; Skin; Specificity; Spondylarthropathies; Staphylococcus aureus; Stimulus; Streptococcus Group B; Structure; Syndrome; Synovial Membrane; Systemic Lupus Erythematosus; T cell response; T-Cell Receptor; T-Lymphocyte; TLR2 gene; TLR3 gene; Testing; Time; Tissues; Toll-Like Receptor 2; Toll-like receptors; Transgenic Mice; Transgenic Organisms; Tropism; Uveitis; Variant; Veterans; Viral; Virus; Wild Type Mouse; Work; Yeasts; Zymosan; adaptive immunity; aggrecan; arthropathies; cytokine; dectin 1; early onset; follow-up; human TLR8 protein; in vitro Assay; in vivo Model; innate immune function; meetings; member; microbial; mucosa-associated lymphoid tissue lymphoma; novel; nucleotide receptor; oligoadenylate; pathogen; protein protein interaction; public health relevance; receptor; receptor function; research study; response; transcription factor; viral RNA

DESCRIPTION (provided by applicant): The etiology and pathogenesis of most types of inflammatory arthritis remain speculative. The role of the adaptive immune system in inflammatory arthritis has been extensively studied. Recently, the innate immune system has been recognized as a possible critical component to initiating or sustaining chronic inflammatory arthritis. The innate immune system is activated by pattern recognition receptors, including NOD- like receptors (NLR) and Toll-like receptors (TLR). This application focuses on one NLR, nucleotide oligomerization domain-2 (NOD2). NOD2 is an intracellular molecule that detects muramyl dipeptide (MDP), a breakdown product of bacterial cell walls, and activates host defenses. NOD2 also plays a critical regulatory role in the control of immune homeostasis. This is known because mutations in NOD2 cause Blau syndrome (a disease characterized by inflammatory arthritis, and inflammation in the skin and uveal track of the eye), and are associated with Crohn's disease, atopic disorders (allergy, asthma and eczema), and possibly colorectal cancer. NOD2 is also expressed in atheroma lesions of patients with coronary artery disease. During the current period of Merit Review funding the principal investigator (PI) identified a novel protein-protein interaction between NOD2 and OAS2, a protein involved in the innate immune response to viruses. This proposal describes studies to follow-up on this observation. Also during the current funding period, using a model of arthritis triggered by an adaptive immune response to proteoglycan aggrecan, the PI found arthritis was worsened when NOD2 was activated by MDP. Studies in this proposal will continue to explore the role of NOD2 in the control of immune homeostasis and inflammatory arthritis. The following experiments are proposed. 1) The nature of the interaction between NOD2-OAS2 will be investigated using biochemical approaches. The ability of each protein to influence the activity of the other in innate immune functions will be investigated. 2) Using normal and NOD2 knockout mice, analyze inflammatory arthritis triggered by intra-articular injection of peptidoglycan from cell walls of Gram positive bacteria, b) zymosan and c) double stranded viral RNA and d) by systemic administration of live Group B streptococci. The role of NOD2 in influencing several parameters of inflammation will be evaluated. The course of arthritis when NOD2 is intentionally activated by intra-articular MDP will be characterized as will the specificity of suppression following NOD2 activation by systemic administration of MDP. Potential Impact on Veterans Health Care: Chronic inflammatory conditions causing arthritis, uveitis, dermatitis, inflammatory bowel disease, asthma and coronary artery lesions represent a significant health issue for veterans. Genetic studies have shown that NOD2 is critical to controlling chronic inflammation in multiple organs. Understanding how NOD2 controls the development of inflammation leading to tissue injury and pathology will have broad implications for the health of veterans. PUBLIC HEALTH RELEVANCE: Chronic inflammatory conditions causing arthritis, uveitis, dermatitis, inflammatory bowel disease, asthma and coronary artery lesions represent a significant health issue for veterans. Genetic studies have shown that NOD2 is critical to controlling chronic inflammation in multiple organs. Understanding how NOD2 controls the development of inflammation leading to tissue injury and pathology will have broad implications for the health of veterans.

描述（由申请人提供）： 大多数类型的炎症性关节炎的病因和发病机制仍然是推测性的。适应性免疫系统在炎症性关节炎中的作用已被广泛研究。最近，先天免疫系统已被认为是引发或维持慢性炎症性关节炎的可能关键组成部分。先天免疫系统由模式识别受体激活，包括 NOD 样受体 (NLR) 和 Toll 样受体 (TLR)。本申请重点关注一种 NLR，即核苷酸寡聚化结构域 2 (NOD2)。 NOD2 是一种细胞内分子，可检测壁酰二肽 (MDP)（细菌细胞壁的分解产物）并激活宿主防御。 NOD2 在免疫稳态的控制中也发挥着关键的调节作用。这是已知的，因为 NOD2 的突变会导致布劳综合征（一种以炎症性关节炎、皮肤和眼睛葡萄膜炎症为特征的疾病），并且与克罗恩病、特应性疾病（过敏、哮喘和湿疹）相关，并且可能与克罗恩病、特应性疾病（过敏、哮喘和湿疹）相关。结直肠癌。 NOD2也在冠状动脉疾病患者的动脉粥样硬化病变中表达。 在当前的优异评审资助期间，首席研究员 (PI) 发现了 NOD2 和 OAS2 之间的一种新型蛋白质-蛋白质相互作用，OAS2 是一种参与对病毒的先天免疫反应的蛋白质。该提案描述了针对这一观察结果的后续研究。此外，在当前资助期间，PI 使用由对蛋白聚糖聚集蛋白聚糖的适应性免疫反应引发的关节炎模型发现，当 MDP 激活 NOD2 时，关节炎会恶化。本提案中的研究将继续探索NOD2在控制免疫稳态和炎症性关节炎中的作用。 建议进行以下实验。 1) 将使用生化方法研究NOD2-OAS2之间相互作用的性质。将研究每种蛋白质影响另一种蛋白质在先天免疫功能中的活性的能力。 2) 使用正常和 NOD2 敲除小鼠，分析关节内注射来自革兰氏阳性菌细胞壁的肽聚糖、b) 酵母聚糖和 c) 双链病毒 RNA 和 d) 通过全身施用活 B 族链球菌引发的炎症性关节炎。将评估 NOD2 在影响炎症的几个参数中的作用。当NOD2被关节内MDP有意激活时关节炎的病程将被表征为通过全身施用MDP对NOD2激活后抑制的特异性。 对退伍军人医疗保健的潜在影响：引起关节炎、葡萄膜炎、皮炎、炎症性肠病、哮喘和冠状动脉病变的慢性炎症对退伍军人来说是一个重大的健康问题。遗传学研究表明，NOD2 对于控制多个器官的慢性炎症至关重要。了解 NOD2 如何控制导致组织损伤和病理的炎症发展将对退伍军人的健康产生广泛的影响。 公共卫生相关性： 引起关节炎、葡萄膜炎、皮炎、炎症性肠病、哮喘和冠状动脉病变的慢性炎症对退伍军人来说是一个重大的健康问题。遗传学研究表明，NOD2 对于控制多个器官的慢性炎症至关重要。了解 NOD2 如何控制导致组织损伤和病理的炎症发展将对退伍军人的健康产生广泛的影响。