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Complement C1q and sepsis associated fatalities

补充 C1q 和脓毒症相关死亡

基本信息

批准号：
10832821
负责人：
Minsoo Kim
金额：
$ 7.95万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-11-15
项目状态：
已结题

项目摘要

1 Complement C1q and sepsis associated fatalities 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.

1 补体C1q与脓毒症相关死亡脓毒症是一种危及生命的全身性炎症性疾病，感染虽然导致疾病的关键性炎症性器官功能障碍病理已经发现，综合征往往难以识别，目前，已发表的预后标准很难识别那些注定死于这种疾病的人。继续我们在改善脓毒症疾病预后方面的努力失败主要是由于患者反应的异质性。即使年龄、性别和合并症相似，尽管有很好的支持性努力，但患者死亡率存在很大的异质性。在这里，（1）我们发现在危重病人中出现了一个CD49c+中性粒细胞亚群，独立预测败血症的死亡率。(2)我们进一步发现，与脓毒症死亡相关的亚群显著上调了补体成分C1q。(3)重要的是，脓毒症幸存者的中性粒细胞表达更高， C1q蛋白水平，而死亡患者未能维持C1q表达，中性粒细胞(4)在小鼠脓毒症模型中，用中和抗体或条件性阻断C1q 敲除中性粒细胞中的C1q导致脓毒性死亡率显著增加。(5)治疗感染C1q的脓毒症小鼠的存活率显著增加。根据这些初步观察，我们的总体假设是，中性粒细胞C1q是脓毒症的可靠预后生物标志物， mortality.进一步假设，凋亡的中性粒细胞释放C1q来控制它们的凋亡。脓毒症期间严重受损器官的自身清除率。因此，C1q是一个药物靶点用于减轻脓毒症患者的炎性损伤，生存在目的1中，我们将确定外周血中C1q表达与 ICU患者的中性粒细胞和脓毒症死亡率。目标2将研究 C1q调节脓毒症的消退，包括C1q依赖的细胞凋亡的吞噬作用嗜中性粒细胞和巨噬细胞的分化。目标3将研究潜在的机制， C1q表达不均一。目的4：研究重组C1q及其突变体的作用对败血症小鼠存活率的影响。总的来说，这一建议涉及机制问题，关于失调的宿主反应如何威胁患者的生存，并提供了一个分子抑制过度炎症反应的破坏性武器，同时促进疾病消退和组织恢复。