Complementopathies: biology, biomarkers, and targets

补体病：生物学、生物标志物和靶标

• 批准号: 10687425
• 负责人: ROBERT A BRODSKY
• 金额: $ 36.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687425
• 关键词: Address; Affect; Alternative Complement Pathway; American Society of Hematology; Antibodies; Anticoagulation; Antiphospholipid Syndrome; Autoantibodies; Biological; Biological Assay; Biological Markers; Biology; Blood Platelets; COVID-19; COVID-19 patient; Cells; Clinical Trials; Cold Hemagglutinin Disease; Complement; Complement 2; Complement Activation; Complement Inactivators; Complement component C5; Data; Diagnosis; Disease; Disease remission; Endothelium; Event; Failure; Frequencies; Funding; Genes; Genotype; Germ-Line Mutation; Goals; HELLP Syndrome; Hematological Disease; Hemolysis; Hemolytic-Uremic Syndrome; Human; Immunoglobulin G; Inflammation; Inflammatory; Injury; Laboratories; Laboratory Research; Lead; Liver Function Tests; Measures; Microcirculation; Organ; Pathogenicity; Patients; Pharmacotherapy; Phenotype; Proteins; Recurrence; Regulation; Regulator Genes; Research; Research Project Grants; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Seminal; Syndrome; Testing; Thrombosis; Time; Translating; Translational Research; Variant; Work; anti-IgG; anti-IgM; arteriole; base; body system; first-in-human; improved; insight; new therapeutic target; novel marker; novel therapeutics; paroxysmal nocturnal hemoglobinuria; precision medicine; severe COVID-19; standard of care; targeted treatment; therapeutic target; thrombotic; translational goal; venule

The overall goal of this competitive renewal is to define the biology of antiphospholipid antibody syndrome, catastrophic antiphospholipid antibody syndrome and severe forms of COVID-19, and to discover novel biomarkers and therapeutic targets. Complementopathies are diseases where end-organ damage is driven by failure to regulate complement on host cells and complement inhibition mitigates cellular and end-organ damage. Classic examples include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (ahUS), and cold agglutinin disease (CAD). Complementopathies are frequently triggered by inflammation and are often associated with a severe thrombotic phenotype, often in the microcirculation. A hallmark is the presence of microthrombi in venules and arterioles due to endothelial injury (thrombotic microangiopathy). Our previously funded submission entitled, Complementopathies: genotype and phenotype, led to a number of seminal discoveries. We validated and refined a cell-based assay (modified Ham test, mHam) that measures complement regulation on human cells, and established the HELLP (hemolysis elevated liver function tests and low platelets) syndrome, antiphospholipid antibody syndrome (APS), catastrophic antiphospholipid antibody syndrome (CAPS), and most recently, severe COVID-19 as complementopathies. The mHam was validated because diseases with a positive mHam were found to have and increase in germline mutations in complement regulatory genes (aHUS, HELLP), an antibody or protein that activates complement (anti-?2-GPI antibodies, COVID-19) or both a germline mutation and an antibody (CAPS). Furthermore, we were able to change standard of care for aHUS by demonstrating that terminal inhibition can be discontinued in most aHUS patients. This proposal is a natural extension of our previously funded work and seeks to extend this work by addressing many unresolved questions in the field. Specifically, we will: 1) develop more reliable biomarkers for APS/CAPS by defining which APS autoantibodies activate complement; 2) identify APS patients who may not require lifelong anticoagulation; 3) prove that germline mutations in complement regulatory genes are common in CAPS; 4) prove that end-organ damage/microvascular thrombosis/endothelial damage from SARS-CoV-2 infection is due to unregulated activity of complement; and 5) demonstrate that germline mutations in complement regulatory genes are more common in patients with more severe forms of COVID19. If funded, we expect to translate our findings into clinical trials that lead to approved drugs for the treatment of severe APS/CAPS, and COVID19.

这种竞争性更新的总体目标是定义抗磷脂抗体综合征的生物学，即 灾难性的抗磷脂抗体综合征和严重形式的Covid-19，并发现新颖的 生物标志物和治疗靶标。互补病是最终器官损害的疾病 无法调节对宿主细胞的补充并补充抑制作用会减轻细胞和末端器官损伤。 经典的例子包括阵发性夜间血红蛋白尿（PNH），非典型溶血性尿毒症综合征 （AHUS）和冷凝集素疾病（CAD）。互补病经常是由炎症和 通常在微循环中与严重的血栓表型有关。标志是存在 由于内皮损伤（血栓形成微型血管病），静脉和小动脉中的微杆菌我们以前 资助的提交标题为互补病：基因型和表型，导致了许多开创性 发现。我们验证并完善了基于细胞的测定（修改后的HAM测试，MHH），该测定法 对人类细胞的调节，并建立了HELLP（溶血升高肝功能测试和低血小板） 综合征，抗磷脂抗体综合征（AP），灾难性抗磷脂抗体综合征 （CAPS），最近是严重的Covid-19作为互补病。 Mham得到了验证，因为 发现具有阳性MHH的疾病具有补体调节性种系突变的增加和增加 基因（Ahus，Hellp），一种激活补体（抗2-GPI抗体，covid-19）的抗体或蛋白质 种系突变和抗体（CAPS）。此外，我们能够改变护理标准 通过证明大多数AHUS患者可以停止终端抑制，AHUS。该建议是 我们以前资助的工作的自然扩展，并试图通过解决许多未解决的问题来扩展这项工作 在现场的问题。具体而言，我们将：1）通过定义哪个 APS自动抗体激活补体； 2）确定可能不需要终身抗凝治疗的APS患者； 3）证明补体调节基因中的种系突变在CAP中很常见； 4）证明最终器官 SARS-COV-2感染造成的损伤/微血管血栓形成/内皮损害是由于活性不受监管的 补充； 5）证明补体调节基因中的种系突变更为常见 在具有更严重形式的covid19的患者中。如果资助，我们希望将我们的发现转化为临床试验 这导致了批准的药物治疗严重的AP/CAP和COVID19。