Complement C1q and sepsis associated fatalities

补充 C1q 和脓毒症相关死亡

• 批准号: 10515703
• 负责人: Minsoo Kim
• 金额: $ 66.56万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515703
• 关键词: Acute; Address; Adult; Age; Antibiotic Therapy; Apoptotic; Blood; Cessation of life; Child; Chronic; Complement; Complement 1q; Complement Activation; Critical Care; Critical Illness; Disease; Enrollment; Failure; Functional disorder; Gene Expression; Heterogeneity; Homeostasis; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Investigational Therapies; Laboratories; Lead; Life; Longitudinal Studies; Measures; Medical; Modeling; Molecular Target; Morbidity - disease rate; Mus; Neutrophil Infiltration; Organ; Organ failure; Pathology; Pathway interactions; Patient Triage; Patients; Phagocytosis; Prevention; Prognosis; Prognostic Marker; Proteins; Publishing; Recombinants; Recovery; Research Design; Resolution; Role; Sepsis; Severity of illness; Site; Subgroup; Supportive care; Survivors; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Variant; arm; attenuation; base; clinical care; comorbidity; conditional knockout; diagnostic criteria; disease prognosis; druggable target; experimental study; high risk; improved; in vivo; insight; longitudinal analysis; macrophage; microbiome; mortality; mortality risk; mutant; neutralizing antibody; neutrophil; organ injury; patient population; patient response; patient subsets; peripheral blood; preservation; prognostic; response; risk stratification; septic; septic patients; severe injury; sex; systemic inflammatory response

PROJECT SUMMARY Sepsis is a life-threatening systemic inflammatory condition with dysregulated host responses to an infection. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been discovered, the syndrome is often difficult to recognize, and current published prognostic criteria poorly identify those destined to die with the condition. Continued failure of our efforts in improving disease prognosis in sepsis is mainly due to substantial heterogeneity in the patient response. Even with similar age, sex, and medical comorbidities, there is a substantial heterogeneity in the patient mortality despite excellent supportive efforts. Here, (1) we discovered that a subpopulation of CD49c+ neutrophil arising in critically ill patients independently predicts mortality from sepsis. (2) We further found that the neutrophil subpopulation associated with septic fatality dramatically upregulated gene expression of the complement component C1q. (3) Importantly, neutrophils from septic survivors expressed higher levels of C1q protein, while deceased patients failed to maintain C1q expression in their neutrophils. (4) In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. (5) Treatment of septic mice with C1q drastically increased the survival. Based on these preliminary observations, our overarching hypothesis is that neutrophil C1q is a reliable prognostic biomarker of septic mortality. It is hypothesized further that apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis. Thus, C1q is a druggable target for attenuation of inflammatory damage to septic patients with resulting improvement in survival. In Aim 1, we will determine the correlation between C1q expression in peripheral blood neutrophils and sepsis mortality in ICU patients. Aim 2 will investigate the mechanisms by which C1q regulates the resolution of sepsis, including C1q-dependent phagocytosis of apoptotic neutrophils and differentiation of macrophages. Aim 3 will investigate mechanisms underlying the heterogenous C1q expression. Aim 4 will determine the effects of recombinant C1q and its mutant variants on the survival of septic mice. Taken together, this proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while promoting disease resolution and tissue recovery.

项目摘要 败血症是一种威胁生命的全身性炎症状况，宿主对感染的反应失调。 尽管已经发现了驱动疾病病理学的关键基于高炎症的器官功能障碍，但 该综合征通常很难识别，并且当前发表的预后标准很差。 注定要死于这种情况。我们在改善败血症疾病预后的努力的持续失败是 主要是由于患者反应的实质性异质性。即使年龄相似，性和医学 合并症，尽管有出色的支持努力，但患者死亡率仍然存在很大的异质性。 在这里，（1）我们发现在重症患者中产生的CD49C+中性粒细胞的亚群 预测败血症的死亡率。 （2）我们进一步发现，中性粒细胞亚群与化粪池有关 补体成分C1q的死亡急剧上调基因表达。 （3）重要的是， 脓毒症幸存者的嗜中性粒细胞表达了更高水平的C1Q蛋白，而已故患者未能 保持中性粒细胞中的C1Q表达。 （4）在鼠标败血症模型中，阻止C1Q进行中和 抗体或有条件敲除中性粒细胞中的C1q导致败血性死亡率显着增加。 （5） 用C1Q治疗化粪池小鼠会大大增加生存率。基于这些初步观察， 我们的总体假设是中性粒细胞C1q是化粪池死亡率的可靠预后生物标志物。它 进一步假设凋亡中性粒细胞释放C1q，以控制自己的清除 败血症期间受伤的器官。因此，C1q是衰减炎症性损害的可药物目标 为化粪池患者，导致生存率提高。在AIM 1中，我们将确定 ICU患者的外周血中性粒细胞和败血症死亡率中的C1Q表达。 AIM 2将调查 C1Q调节败血症分辨率的机制，包括依赖C1Q的吞噬作用 凋亡中性粒细胞和巨噬细胞的分化。 AIM 3将调查基础的机制 异源C1Q表达。 AIM 4将确定重组C1Q及其突变变体对 化粪池小鼠的生存。综上 宿主反应威胁患者的生存，并提供了一个分子靶标，以抑制 高炎症反应，同时促进疾病分辨率和组织恢复。