Alpha B crystallin as a novel therapeutic for SIRS and Sepsis

Alpha B 晶状体蛋白作为 SIRS 和脓毒症的新型疗法

• 批准号: 8129849
• 负责人: JONATHAN B ROTHBARD
• 金额: $ 27.58万
• 依托单位: CARDINAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129849
• 关键词: Accounting; Acute-Phase Proteins; Animal Model; Animals; Anti-Inflammatory Agents; Bacterial Infections; Binding; Biological Assay; Biological Response Modifier Therapy; C-reactive protein; Cessation of life; Clinical; Clinical Trials; Coagulation Process; Complement; Complex; Data; Disease; Dose; Foundations; Grant; Heat shock proteins; Human; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Intensive Care Units; Interleukin-6; Link; Mass Spectrum Analysis; Modeling; Molecular Chaperones; Monitor; Multiple Sclerosis; Mus; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Point Mutation; Principal Investigator; Protein C; Protein Family; Proteins; Reperfusion Injury; Rheumatoid Arthritis; Role; Sepsis; Septic Shock; Septic Toxemia; Serological; Serum amyloid A protein; Severities; Severity of illness; Site; Specificity; Stimulus; Stroke; Temperature; Therapeutic; Time; Trauma; activated Protein C; alpha-Crystallin B Chain; base; cytokine; drug candidate; inflammatory modulation; member; novel; novel therapeutics; optimism; pre-clinical; progression marker; prospective; research study; serological marker

DESCRIPTION (provided by applicant): Alpha B crystallin (Cryab), a member of the small heat shock protein family, recently has been shown to be a broad based anti-inflammatory agent effective in animal models of multiple sclerosis, rheumatoid arthritis, ischemia-reperfusion injury, and stroke. The basis of this proposal is to establish whether Cryab is effective in models of LPS toxemia and bacterial sepsis. The aims of the grant are first to demonstrate that Cryab, and not Cryab with a point mutation at residue 120, can (i.) reduce in a dose dependent manner serological levels of IL-6, serum amyloid A, and C reactive protein in mice injected with LPS and (ii.) extend the lifetime of animals administered lethal doses of LPS compared with untreated animals. The second aim is to establish the relevance of the potency of Cryab by comparing the modulation of inflammatory cytokines with that observed for treatment with murine activated protein C. Activated protein C is the only approved drug for sepsis and any prospective therapeutic must be equally or more potent. In addition, we propose to determine whether Cryab and activated protein C could act synergistically by the co-administrating of the two proteins. The last aim is to assay the levels of Cryab in murine plasma at various times after injection with LPS to determine whether the protein is a marker of the severity of the disease and also support the hypothesis that Cryab has a natural role in modulating inflammation. In addition, Cryab levels in plasma from human trauma patients will be monitored to determine whether this protein can be used as a marker for progression of SIRS into septic shock. The mode of action of Cryab appears to be linked with the protein's role as a chaperone. The ability of the small heat shock proteins to bind partially unfolded proteins and lower their concentration at sites of inflammation and consequently limit aggregation and the inflammatory stimulus. Using mass spectrometry we have demonstrated that Cryab binds between 50 and 75 different plasma proteins in a temperature dependent fashion, with the vast majority being acute phase proteins or members of the complement or coagulation cascades. Analyzing the supernatants of these pull down experiments demonstrate that the concentration of many of the plasma proteins was reduced significantly. This data provides scientific foundation that Cryab can be distinguished from the large number of potential therapeutics that have not achieved their clinical milestones in this complex disease. We believe that the broad specificity of alpha B crystallin could enable the protein to be an effective therapeutic for sepsis and SIRS. PUBLIC HEALTH RELEVANCE: Sepsis, a complex dysregulation of inflammation resulting from the host response to a bacterial infection or severe trauma, is responsible for over half of the deaths in intensive care units accounting for more than 200,000 deaths per year. Over 30 different clinical trials of anti-inflammatory agents have failed during the past twenty years. This proposal seeks to provide preclinical support that a novel biotherapeutic, alpha B crystallin, can be an effective drug for sepsis. The intellectual framework for this optimism is the protein's capacity to modulate a far wider range of inflammatory mediators in plasma than the drug candidates used in previous clinical trials resulting in significant reductions of the serological markers of this complex disease.

描述（由申请人提供）：α B晶体蛋白（Cryab）是小热休克蛋白家族的一员，最近已被证明是一种广泛的抗炎剂，对多发性硬化症、类风湿性关节炎、缺血再灌注损伤和中风的动物模型有效。本研究的基础是确定Cryab在LPS毒血症和细菌性败血症模型中是否有效。该基金的目的是首先证明Cryab，而不是在残基120位点有点突变的Cryab，可以(i)以剂量依赖的方式降低注射LPS小鼠的血清IL-6、血清淀粉样蛋白a和C反应蛋白水平，（ii）与未治疗的动物相比，延长注射致死剂量LPS的动物的寿命。第二个目的是通过比较炎症细胞因子的调节与小鼠活化蛋白C治疗观察到的效果来建立Cryab效力的相关性。活化蛋白C是唯一被批准用于败血症的药物，任何前瞻性治疗必须具有同等或更强的效力。此外，我们提出确定Cryab和活化蛋白C是否可以通过共同给药来协同作用。最后一个目的是在注射LPS后不同时间测定小鼠血浆中Cryab的水平，以确定该蛋白是否是疾病严重程度的标志，并支持Cryab在调节炎症中具有天然作用的假设。此外，将监测人类创伤患者血浆中的Cryab水平，以确定该蛋白是否可作为SIRS进展为感染性休克的标志物。