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.

项目摘要 Purpura Fulminans（PF）是败血症的一种罕见但毁灭性的并发症，其中患者 发展出高度血栓形成亚型的亚型的血管内凝血（DIC），导致 肢解，最终器官损坏和死亡。 PF可以由一系列细菌触发 感染，并以极高的循环细胞因子和钥匙失效为特征 抗炎途径引起引起凝组织因子的明显上调 （TF）激活的单核细胞表达。因为PF代表了极端疾病的表型，所以 利用我们在这种疾病中的发现可以产生对化粪池更广泛问题的关键见解 DIC。然而，目前几乎没有关于分子病理生理学和 遗传易感性PF。利用种系整个外显点测序（WES）和A 有针对性的基因发现方法，我们发现稀有，有害的富集很大 与未选择的患者相比，PF患者的补体系统中的编码变体 败血症（p <0.0001）。有趣的是，我们还发现这些变体可能与 尽管没有明显的PF，但未选择的败血症患者的死亡率增加。我们 假设补体系统缺陷导致系统性炎症增加，并且 促凝活性，导致凝血病的发展。在该项目的目标1中，我们 将通过对临床上良好的宣传来跟进我们的初步结果 NHLBI Biolincc存储库中的标本来自化粪池患者，没有明显的PF。我们将 将补体状态与血栓形成和炎症的血浆生物标志物相关联 调整了年龄，性别，种族和合并症之后，以了解是否补充 系统缺陷与败血症中的血栓炎性恶化有关。在AIM 2中，我们将 在功能上表征了补体受体中新型稀有PF相关的变体3 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。 拟议的工作将为天生之间的关系提供重要的新见解 免疫力和失调的凝血，并与基础WES数据集生成 研究败血症中凝血病的广泛问题的生物学相关。