Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans

阐明遗传性​​补体系统缺陷在败血症和暴发性紫癜分子病理生理学中的作用

• 批准号: 10044028
• 负责人: Pavan Bendapudi
• 金额: $ 13.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044028
• 关键词: Address; Age; Anti-Inflammatory Agents; Anticoagulation; Bacterial Infections; Biological; Biological Markers; Blood Coagulation Disorders; Cells; Cessation of life; Clinical; Coagulation Process; Code; Complement; Complement component C1; Complication; Data; Data Set; Defect; Development; Disease; Disseminated Intravascular Coagulation; Ethnic Origin; Factor Xa; Failure; Foundations; Functional disorder; Generations; Genetic; Genetic Predisposition to Disease; Goals; Human; Individual; Infection; Inflammation; Inflammatory; Inherited; Integrins; Intervention; Lead; Link; Macrophage-1 Antigen; Molecular; Molecular Profiling; Mutation; National Heart, Lung, and Blood Institute; Natural Immunity; Neisseria meningitidis; Organ; Pathway interactions; Patients; Pattern; Plasma; Play; Population; Production; Proteins; Public Health; Purpura Fulminans; Research; Role; Sepsis; Signal Pathway; Signal Transduction; Specimen; Streptococcus pneumoniae; Therapeutic Intervention; Thromboplastin; Thrombosis; U937 Cells; Up-Regulation; Variant; Work; biobank; clinical predictors; cohort; comorbidity; comorbidity Index; complement pathway; complement system; cytokine; disease phenotype; exome sequencing; follow-up; gain of function; gene discovery; immunoregulation; insight; loss of function; macrophage; monocyte; mortality; mutant; mutational status; novel; pathogen exposure; pathogenic microbe; receptor; repository; response; septic; septic patients; sex; thromboinflammation; trend

PROJECT SUMMARY Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients develop a highly thrombotic subtype of disseminated intravascular coagulation (DIC), leading to dismemberment, end organ damage, and death. PF can be triggered by a range of bacterial infections and is distinguished by extremely high levels of circulating cytokines and failure of key anti-inflammatory pathways which cause a marked upregulation of procoagulant tissue factor (TF) expression by activated monocytes. Because PF represents an extreme disease phenotype, leveraging our findings in this disorder could yield key insights into the broader problem of septic DIC. However, at present almost nothing is known about the molecular pathophysiology and genetic predisposition underlying PF. Utilizing germline whole exome sequencing (WES) and a targeted gene discovery approach, we have found a significant enrichment in rare, deleterious coding variants in the complement systems of patients with PF compared to unselected patients with sepsis (P<0.0001). Intriguingly, we also found that these variants may be associated with increased mortality in unselected sepsis patients despite the absence of overt PF. We hypothesize that complement system defects lead to heightened systemic inflammation and procoagulant activity, resulting in the development of coagulopathy. In Aim 1 of this project, we will follow up on our preliminary results by performing WES on clinically well-annotated specimens in the NHLBI BioLINCC repository from septic patients without overt PF. We will correlate complement mutational status to plasma biomarkers of thrombosis and inflammation after adjusting for age, sex, ethnicity, and comorbidities in order to understand if complement system defects are associated with worsened thrombo-inflammation in sepsis. In Aim 2, we will functionally characterize a novel class of rare PF-associated variants in complement receptors 3 and 4 (CR3/4) with respect to their impact on monocyte-driven inflammation and thrombosis. The proposed work will provide important new insights into the relationship between innate immunity and dysregulated coagulation and generate a foundational WES dataset with biological correlates for studying the widespread problem of coagulopathy in sepsis.

项目总结 暴发性紫癜(PF)是脓毒症的一种罕见但毁灭性的并发症，患者 发展为高度血栓性的弥散性血管内凝血(DIC)亚型，导致 肢解，结束器官损伤，和死亡。由一系列细菌引起的肺泡炎 感染，以极高的循环细胞因子水平和密钥失败为特征 导致促凝血剂组织因子显著上调的抗炎途径 活化的单核细胞表达(Tf)。因为PF代表了一种极端的疾病表型， 利用我们在这种疾病中的发现，可以对更广泛的脓毒症问题产生关键的见解 迪克。然而，目前对其分子病理生理学和分子生物学的研究几乎一无所知。 遗传易感性是PF的潜在原因。利用生殖系完整外显子组测序(WES)和 有针对性的基因发现方法，我们发现了一种显著的稀有、有害的富集物 PF患者补体系统中的编码变异与未选择的患者的比较 合并败血症(P&lt；0.0001)。有趣的是，我们还发现这些变异可能与 未选择的脓毒症患者的死亡率增加，尽管没有明显的肺功能衰竭。我们 补体系统缺陷会导致全身性炎症加重和 促凝血活性，导致凝血障碍的发展。在这个项目的目标1中，我们 将跟进我们的初步结果，通过对临床注释良好的患者进行WES NHLBI BioLINCC资料库中来自无明显PF的败血症患者的样本。我们会 补体突变状态与血栓形成和炎症的血浆生物标志物的相关性 在调整了年龄、性别、种族和合并症后，以了解是否补充 系统缺陷与脓毒症中血栓炎症的恶化有关。在目标2中，我们将 补体受体3中一类新的罕见的Pf相关变异体的功能特征 和4(CR3/4)，关于它们对单核细胞驱动的炎症和血栓形成的影响。 这项拟议的工作将为研究先天不足之间的关系提供重要的新见解。 免疫和凝血失调，并生成一个基本的WES数据集 研究脓毒症中普遍存在的凝血障碍问题的生物学相关性。