Validation of extracellular histones as biomarker and therapeutic target in sepsi

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题，03-HL-101：确定和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标记物本申请侧重于细胞外组蛋白在脓毒症病理生理学中的新作用，尤其旨在确认组蛋白作为严重脓毒症和伴随的多器官功能障碍或衰竭(MODS/MOF)的生物标记物、介体和治疗靶点。严重的脓毒症是一个主要的医疗问题，每年导致美国约75万名ICU患者入院，造成超过170亿美元的损失和22.5万人死亡。我们的团队最近发现，核组蛋白在细胞外环境中释放，以应对炎症挑战，是脓毒症引起的器官衰竭和死亡的重要介质。组蛋白血浆水平与动物(小鼠和狒狒)以及患有败血症的人类的器官功能障碍和死亡有关。Xgris(激活蛋白C)可裂解组蛋白并降低其毒性。用抗体或封闭肽抑制组蛋白使小鼠免于实验性致死性脓毒症。这项建议的目的是：(I)验证细胞外组蛋白作为重要的生物标志物，介导组织损伤，最终导致器官衰竭，以及(Ii)表征两种组蛋白阻断策略的治疗潜力。目的1在四种脓毒症小鼠模型上，采用外源性组蛋白攻击的方法，研究组蛋白的体内细胞毒性、炎症和微血栓形成作用以及组蛋白的治疗靶向性。目的2将组蛋白抑制方法转化为大型动物中临床相关的大肠杆菌败血症模型。目的3.将血浆组蛋白确认为器官功能障碍的预后生物标志物，与临床结果相关，并有助于确定哪些患者将受益于使用组蛋白阻断的特定抗菌治疗。总体而言，该项目将促进对脓毒症所致器官损害的病理生理学的了解，将验证新的生物标志物，并为脓毒症和多器官功能衰竭患者开发一种新的潜在治疗方法。 与公共卫生相关：脓毒症是一种多因素的疾病，会触发不受控制的炎症反应，最终导致多器官衰竭和死亡。我们有证据表明，在脓毒症期间，组蛋白在细胞外环境中释放，是器官功能障碍和致命性的媒介。这项建议的目的是验证细胞外组蛋白作为组织损伤的重要原因和生物标记物，并测试两种组蛋白阻断方法作为脓毒症的潜在治疗方法。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction This application focuses on the novel role of extracellular histones in the pathophysiology of sepsis, particularly aiming to validate the histones as a biomarker, mediator and therapeutic target for severe sepsis and accompanying multiple organ dysfunction or failure (MODS/MOF). Severe sepsis is a major medical problem responsible for approximately 750,000 ICU admissions at a cost of over 17 billion dollars and 225,000 deaths in the U.S. annually. Our group has recently discovered that nuclear histones are released in the extracellular environment in response to inflammatory challenges and are important mediators of sepsis-induced organ failure and death. Histone plasma levels correlate with organ dysfunction and death in animals (mice and baboons), as well as in humans with sepsis. Xigris (activated protein C) cleaves histones and reduces their toxicity. Histone inhibition with antibodies or blocking peptides rescue mice from experimental lethal sepsis. The objectives of this proposal are: (i) to validate extracellular histones as important biomarkers that mediate of tissue damage, ultimately leading to organ failure, and (ii) characterize the therapeutic potential of two histone blocking strategies. Aim 1 employs exogenous histone challenge to characterize the in vivo cytotoxic, inflammatory and microthrombotic effects of histones and therapeutic targeting of histones in four mouse models of sepsis. Aim 2 will translate the histone inhibition approaches to a clinically relevant model of E. coli sepsis in a large animal. Aim 3. Will validate the plasma histones as a prognostic biomarker for organ dysfunction that correlates with clinical outcomes, and helps to identify the patients who will benefit from specific antisepsis therapies with histone blockade. Overall, this project will advance the understanding of the pathophysiology of sepsis induced organ damage, will validate new biomarkers and develop a novel potential treatment for patients with sepsis and MOF. PUBLIC HEALTH RELEVANCE: Sepsis is a multi-factorial disorder that triggers an uncontrolled inflammatory response, ultimately leading to multiple organ failure and death. We have evidence that during sepsis, histones are released in the extracellular environment and are mediators of organ dysfunction and lethality. The objectives of this proposal are to validate extracellular histones as an important cause and biomarker of tissue damage and to test two histone-blocking approaches as potential therapeutics in sepsis.