C-reactive protein in rheumatoid arthritis

类风湿性关节炎中的 C 反应蛋白

• 批准号: 9281652
• 负责人: ALOK AGRAWAL
• 金额: $ 52.62万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-13 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281652
• 关键词: Animal Model; Antigen-Antibody Complex; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Binding; Binding Proteins; Blood; C-reactive protein; Cardiovascular Diseases; Cholesterol; Collagen-Induced Arthritis; Complement; Complement 3a; Complement 3b; Complement 5a; Complement Activation; Data; Deposition; Development; Disease; Engineering; Environment; Foam Cells; Goals; Host Defense; Human; Hydrogen Peroxide; Immobilization; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-17; Investigation; Joints; Knock-out; Knockout Mice; Lesion; Liquid substance; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Measures; Mediating; Mus; Pathologic; Patients; Phagocytes; Plasma Proteins; Production; Research Project Grants; Rheumatoid Arthritis; Role; Site; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Synovial Fluid; T-Lymphocyte; TNF gene; Testing; Variant; cytokine; in vivo; insight; joint destruction; macrophage; mouse model; mutant; novel; prevent; protective effect; protein complex; public health relevance; treatment strategy

 DESCRIPTION (provided by applicant): This research project is on the structure-function relationships of C-reactive protein (CRP) in rheumatoid arthritis (RA) and is focused on the interaction between modified CRP and immune complexes (ICs) and on the possible role of modified CRP in regulating IC-mediated inflammatory responses and development of RA. RA is an autoimmune disease in which autoantibody-mediated inflammation leads to erosive destruction of the joints. CRP is a plasma protein but is also present in the synovial fluid of RA patients. The functions of CRP in RA and whether CRP is always functional while in the synovial fluid are unknown. Immune complexes have been implicated in promoting RA inflammation, in part due to complement activation by ICs and in part due to the binding of ICs to phagocytes resulting in the production of pro-inflammatory cytokines. Using the collagen- induced arthritis (CIA) mouse model of RA, it has been shown that CRP exerts a protective effect during the onset of CIA via undefined mechanisms. We hypothesize that CRP requires a change in its structure and that modified CRP binds to ICs and subsequently controls the pro-inflammatory effects of ICs. Because RA patients are more susceptible to cardiovascular disease and because modified CRP also binds to atherogenic low- density lipoprotein (LDL), we hypothesize that modified CRP also controls the pro-inflammatory effects of LDL and can protect against the development of atherosclerosis. Accordingly, the effects of three different exogenously prepared CRP variants on the development of CIA and atherosclerosis in mice will be investigated. These structurally altered CRP variants are: H2O2-treated CRP and two CRP mutants generated by site-directed mutagenesis. These CRP variants, unlike native CRP, are capable of binding to immobilized ICs and atherogenic LDL. Therefore, it is anticipated that the administration of these CRP variants into mice will result in the decrease in complement activation and production of pro-inflammatory cytokines, and that the CRP variants will be more protective than native CRP against the development of CIA and atherosclerosis in mice. In aim 1, we will determine whether exogenously prepared modified CRP capable of binding to ICs is protective against the development of CIA in mice. In aim 2, we will determine whether the binding of modified CRP to ICs reduces the pro-inflammatory effects of ICs. In aim 3, we will determine whether modified CRP capable of binding to atherogenic LDL is protective against the development of atherosclerosis in mice. The overall goal is to provide insight into the possible use of modified CRP in controlling autoantibody-mediated and LDL-mediated inflammation in the joints of RA patients and in the arteries of atherosclerosis patients, respectively, and may open a new line of investigation to explore why endogenous CRP fails to prevent the development of inflammatory diseases.

 描述(申请人提供)：这项研究项目是关于类风湿关节炎(RA)中C-反应蛋白(CRP)的结构-功能关系，重点是修饰的CRP与免疫复合体(IC)之间的相互作用，以及修饰的CRP在调节IC介导的炎症反应和RA发展中的可能作用。类风湿关节炎是一种自身免疫性疾病，自身抗体介导的炎症会导致关节的侵蚀性破坏。CRP是一种血浆蛋白，但也存在于RA患者的滑液中。CRP在RA中的作用，以及在滑液中的CRP是否总是起作用，目前尚不清楚。免疫复合体参与了类风湿关节炎的炎症反应，部分是由于免疫细胞激活补体，部分是由于免疫细胞与吞噬细胞结合，产生促炎细胞因子。在胶原诱导性关节炎(CIA)小鼠RA模型上，已经证明CRP在CIA发病过程中通过未明确的机制发挥保护作用。我们假设，CRP需要改变其结构，修饰后的CRP与ICs结合，从而控制ICs的促炎作用。由于RA患者更易患心血管疾病，而且修饰的CRP还与致动脉粥样硬化的低密度脂蛋白(LDL)结合，因此我们推测，修饰的CRP也可以控制低密度脂蛋白的促炎作用，并可以防止动脉粥样硬化的发展。因此，将研究三种不同的外源制备的CRP变体对小鼠CIA和动脉粥样硬化发展的影响。这些结构改变的CRP变体是：经过氧化氢处理的CRP和两个通过定点突变产生的CRP突变体。这些C反应蛋白变异体与天然C反应蛋白不同，能够与固定的ICs和致动脉粥样硬化的低密度脂蛋白结合。因此，在小鼠体内应用这些C反应蛋白变异体将导致补体激活和促炎细胞因子的产生减少，并且C反应蛋白变异体将比天然的C反应蛋白对小鼠的CIA和动脉粥样硬化具有更好的保护作用。在目标1中，我们将确定外源制备的能够与ICs结合的修饰的CRP是否对小鼠的CIA的发展具有保护作用。在目标2中，我们将确定修饰的CRP与ICs的结合是否会减少ICs的促炎作用。在目标3中，我们将确定能够与致动脉粥样硬化的低密度脂蛋白结合的修饰的CRP是否对小鼠动脉粥样硬化的发展具有保护作用。总体目标是深入了解改良的CRP在RA患者关节和动脉粥样硬化患者的关节和动脉中分别控制自身抗体介导的炎症和低密度脂蛋白介导的炎症的可能性，并可能开辟一条新的研究路线，探索为什么内源性CRP未能预防炎症性疾病的发展。