Structure-Function Relationships of C-Reactive Protein

C反应蛋白的结构-功能关系

• 批准号: 7891153
• 负责人: ALOK AGRAWAL
• 金额: $ 32.18万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891153
• 关键词: Acute-Phase Proteins; Age related macular degeneration; Area; Bacteremia; Bacterial Infections; Binding; C-reactive protein; Cell Wall; Characteristics; Classical Complement Pathway; Clinical Medicine; Complement; Complement 1q; Complement Factor H; Data; Funding; Goals; Human; In Vitro; Infection; Inflammation; Inflammatory; Investigation; Knockout Mice; Lectin; Ligands; Mediating; Modeling; Mus; Mutagenesis; Natural Immunity; Pathway interactions; Phagocytosis; Pneumococcal Infections; Polysaccharides; Principal Investigator; Property; Protein Binding; Protein C; Proteins; Serum; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Surface; Testing; Thinking; base; complement pathway; complement system; in vivo; killings; macrophage; mutant; programs; public health relevance; receptor

DESCRIPTION (provided by applicant): C-reactive protein (CRP) is a component of innate immunity and whose serum level rises during inflammatory states including bacterial infections. In vitro, CRP binds to cell wall C-polysaccharide (PnC) on Streptococcus pneumoniae and subsequently activates the complement system in serum. CRP also binds to complement factor H, the protein that pneumococci also bind to and use to escape complement-mediated killing. In murine models of infection, human CRP is protective against lethal infection with S. pneumoniae. Our long-term goal is to define the mechanisms by which CRP protects against pneumococcal infection in mice. How does CRP, directly or indirectly, act on the bacterial surfaces to kill them? Our hypothesis is that the mechanism of protective action of CRP involves the activation of the complement system. It was assumed that CRP was protective through a pathway in which CRP binds to PnC, activates complement through the classical cascade, and then bacteremia is reduced through complement-dependent phagocytosis. Two observations suggest that this pathway is not sufficient. The mechanism of CRP protection is much more sophisticated than previously appreciated. First, human CRP cannot bind murine C1q and therefore cannot activate the classical complement cascade. Second, a CRP mutant incapable of binding to PnC is still protective against pneumococcal infection in mice. Each of these two intriguing observations will be separately pursued in the following two specific aims. 1. To test the hypothesis that the activation and recruitment of the complement components on the pneumococcal surface, subsequent to the binding of CRP to pneumococci, participate in CRP-mediated protection of mice from pneumococcal infection. 2. To test the hypothesis that the binding of CRP to complement factor H on factor H-coated pneumococci participates in the protection of mice from infection. PUBLIC HEALTH RELEVANCE Our goal is to understand the mechanisms by which the in vitro binding and functional capabilities of C-reactive protein (CRP) relate to its in vivo functions in inflammation. Elucidation of the mechanisms by which CRP protects mice from Streptococcus pneumoniae infections would help achieve our goal. In addition, the investigation of CRP-complement factor H interactions may also have implications in other areas of clinical medicine such as age-related macular degeneration.

描述（由申请人提供）：C反应蛋白（CRP）是先天免疫的一种成分，其血清水平在炎症状态（包括细菌感染）期间升高。在体外，CRP与肺炎链球菌上的细胞壁C-多糖（PnC）结合，随后激活血清中的补体系统。CRP还与补体因子H结合，该蛋白质也与肺炎球菌结合并用于逃避补体介导的杀伤。在感染的鼠模型中，人CRP对S.肺炎。我们的长期目标是确定CRP保护小鼠免受肺炎球菌感染的机制。CRP如何直接或间接作用于细菌表面以杀死它们？我们的假设是CRP的保护作用机制涉及补体系统的激活。据推测，CRP是通过一个途径，其中CRP结合到PnC，激活补体通过经典的级联反应，然后通过补体依赖性吞噬减少菌血症的保护。两个观察结果表明，这一途径是不够的。CRP的保护机制比以前认识到的要复杂得多。首先，人CRP不能结合鼠C1 q，因此不能激活经典的补体级联。第二，不能与PnC结合的CRP突变体在小鼠中仍然对肺炎球菌感染具有保护作用。这两个有趣的观察将分别在以下两个具体目标中进行。1.检验以下假设：CRP与肺炎球菌结合后，肺炎球菌表面补体成分的活化和募集参与CRP介导的小鼠肺炎球菌感染保护。2.检验CRP与H因子包被的肺炎球菌上的补体H因子结合参与保护小鼠免受感染的假设。 公共卫生相关性我们的目标是了解C-反应蛋白（CRP）的体外结合和功能能力与其体内炎症功能相关的机制。阐明CRP保护小鼠免受肺炎链球菌感染的机制将有助于实现我们的目标。此外，CRP-补体因子H相互作用的研究也可能对其他临床医学领域（如年龄相关性黄斑变性）产生影响。