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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：
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.

项目总结