Complement C1q and sepsis associated fatalities

补充 C1q 和脓毒症相关死亡

基本信息

批准号：
10643889
负责人：
Minsoo Kim
金额：
$ 67.09万
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643889
关键词：
Acute Address Adult Age Antibiotic Therapy Apoptotic Blood C1q deficiency Cessation of life Child Chronic Complement Complement 1q Complement Activation Critical Care Critical Illness Disease Failure Functional disorder Gene Expression Heterogeneity Homeostasis Human Immune response Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Investigational Therapies Laboratories Life Longitudinal Studies Macrophage 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 clinical care comorbidity conditional knockout diagnostic criteria disease prognosis druggable target experimental study high risk improved in vivo insight longitudinal analysis microbiome mortality mortality risk mutant neutralizing antibody neutrophil organ injury participant enrollment patient population patient response patient subsets peripheral blood preservation prognostic response risk stratification septic septic patients severe injury sex systemic inflammatory response

项目摘要

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.

项目概要脓毒症是一种危及生命的全身炎症性疾病，宿主对感染的反应失调。尽管已经发现了导致疾病病理的关键的基于过度炎症的器官功能障碍，这种综合征通常很难识别，目前公布的预后标准很难识别那些注定会死于这种情况。我们在改善脓毒症疾病预后方面的努力持续失败主要是由于患者反应的显着异质性。即使年龄、性别和健康状况相似尽管有出色的支持努力，但患者死亡率仍存在很大的异质性。在这里，（1）我们发现危重患者中独立出现的 CD49c+ 中性粒细胞亚群预测脓毒症死亡率。 (2)我们进一步发现中性粒细胞亚群与脓毒症相关死亡显着上调补体成分 C1q 的基因表达。 (3) 重要的是，脓毒症幸存者的中性粒细胞表达较高水平的 C1q 蛋白，而死亡患者则未能表达维持中性粒细胞中的 C1q 表达。 (4) 在小鼠脓毒症模型中，用中和作用阻断 C1q 抗体或有条件敲除中性粒细胞中的 C1q 会导致脓毒症死亡率显着增加。 (5) 用 C1q 治疗脓毒症小鼠可显着提高存活率。根据这些初步观察，我们的首要假设是中性粒细胞 C1q 是脓毒症死亡率的可靠预后生物标志物。它进一步假设凋亡的中性粒细胞释放 C1q 以控制其自身的清除率脓毒症期间损伤的器官。因此，C1q 是减轻炎症损伤的药物靶点脓毒症患者的生存率得到改善。在目标 1 中，我们将确定之间的相关性 ICU 患者外周血中性粒细胞中的 C1q 表达与脓毒症死亡率。目标 2 将调查 C1q 调节脓毒症消退的机制，包括 C1q 依赖性吞噬作用中性粒细胞凋亡和巨噬细胞分化。目标 3 将研究潜在的机制异质 C1q 表达。目标 4 将确定重组 C1q 及其突变变体对脓毒症小鼠的存活。总而言之，该提案解决了有关失调的机制宿主反应威胁着患者的生存，并为抑制宿主的破坏性武器提供了分子靶点高炎症反应，同时促进疾病消退和组织恢复。