Role of mitochondria in SLE and its cardiovascular complications
线粒体在 SLE 及其心血管并发症中的作用
基本信息
- 批准号:10274520
- 负责人:
- 金额:$ 60.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-25 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AerobicAffinityAnaerobic BacteriaAntibodiesAnticardiolipin AntibodiesAntigensAntiphospholipid SyndromeAutoantibodiesAutoantigensAutoimmunityBiological MarkersBiologyBlood PlateletsCardiolipinsCardiovascular DiseasesCardiovascular systemCellsCessation of lifeClinicalCoagulation ProcessComplementComplement 1qDataDevelopmentDiseaseDisease ManagementEarly treatmentEngineeringExcisionExposure toFlow CytometryGenomeImmuneImmune responseImpairmentIn VitroIndividualInflammationInflammatoryLifeLupusMass Spectrum AnalysisMediatingMethionineMitochondriaMitochondrial ProteinsModelingMonitorMusOrganOutcomeOutcome MeasurePathologyPathway interactionsPatientsPhagocytosisPhospholipidsPlatelet ActivationPower PlantsPreventive measurePreventive treatmentProcessProductionPrognostic MarkerProkaryotic CellsPropertyProtein BiosynthesisReactive Oxygen SpeciesResearchRheumatoid ArthritisRiskRoleSamplingSignal PathwaySystemSystemic Lupus ErythematosusTestingThrombosisThrombusVenous ThrombosisWorkbasecohortcomplement systemcytokinedesignexperimental studyextracellularhuman diseaseimmunogenicin vivoin vivo Modelinsightmouse modelneutrophilnew therapeutic targetnovelnovel markerphosphoproteomicsprognostictherapeutic targetvenous thromboembolism
项目摘要
Summary: Upon cellular death, cells release damaged mitochondria, contributing to local
inflammation. The overall aims of the present study are to investigate how mitochondria are
cleared to avoid evoking an aberrant immune response, and to determine if autoantibodies
targeting mitochondrial proteins have clinical utility in assessing development of thrombosis in
patients with systemic lupus erythematosus (SLE). The premise of the study is that SLE patients
have impaired clearance of mitochondria, promoting development of mitochondrial antibodies,
inflammation and organ damage, including thrombosis. To investigate this we have three main
aims. The first aim investigates how mitochondrial extrusion promotes autoimmunity towards
mitochondrial protein antigens, attempting to define the exact target of novel main mitochondrial
autoantibody, AMA-17, the processes involved in exposing the autoantigen in vitro, as well as
potential therapeutic targets, e.g. mitochondrial ROS, involved in generating AMA-17 in vivo.
The second aim investigates how anti-mitochondrial antibodies partake in thrombosis
development. Using a large longitudinal SLE cohort (n=500), followed over 10 years, we will
determine the capacity of AMA-17 to associate with and/or predict development of venous
thrombosis. Affinity-purified AMA-17 antibodies will be tested for platelet activation and
thrombus formation in vitro using flow cytometry, aggregometry and a cutting-edge model of
engineered microvessels, as well as in vivo using a novel model of antibody-mediated venous
thrombosis developed by Dr. Knight. Finally, in Aim 3, we will investigate underlying
mechanisms involved in clearance of mitochondria, with an emphasis on the role of complement
C1q and C3 to facilitate silent clearance. These studies will be done both in vitro using select
isolated complement components, as well as in vivo using unique C1q and C3 deficient mice.
Outcome measures include phagocytosis, cytokine production, and NET formation.
Downstream signaling pathways involved in mitochondrial-mediated inflammation will be
identified using mass spectrometry-based phosphoproteomics. In all, our study aims at
identifying fundamental mechanisms regulating inflammation, thrombosis and autoimmunity in
the context of human disease, with an emphasis on the role of the complement system in silent
removal of mitochondria. We expect the proposed research to provide novel therapeutic targets
disrupting the inflammatory and immunogenic properties of mitochondria, applicable for many
diseases, including SLE and rheumatoid arthritis, as well as identify prognostic mitochondrial-
derived biomarkers enabling early and preventive treatment of venous thrombosis.
总结:细胞死亡后,细胞释放受损的线粒体,导致局部
炎症本研究的总体目标是研究线粒体是如何
清除,以避免引起异常的免疫反应,并确定是否有自身抗体
靶向线粒体蛋白在评估血栓形成的发展中具有临床效用,
系统性红斑狼疮(SLE)患者。研究的前提是SLE患者
线粒体清除受损,促进线粒体抗体的产生,
炎症和器官损伤,包括血栓形成。为了研究这个问题,我们有三个主要的
目标。第一个目的是研究线粒体挤压如何促进自身免疫,
线粒体蛋白抗原,试图确定新的主要线粒体的确切靶点,
自身抗体,AMA-17,涉及体外暴露自身抗原的过程,以及
潜在的治疗靶点,例如线粒体ROS,参与体内产生AMA-17。
第二个目的是研究抗线粒体抗体如何参与血栓形成
发展使用大型纵向SLE队列(n=500),随访10年以上,我们将
确定AMA-17与静脉血栓形成相关和/或预测静脉血栓形成的能力,
血栓形成将测试亲和纯化的AMA-17抗体的血小板活化,
使用流式细胞术、聚集测定法和尖端的
工程化微血管,以及在体内使用抗体介导的静脉
奈特医生发现的血栓最后,在目标3中,我们将研究潜在的
涉及线粒体清除的机制,强调补体的作用
C1 q和C3有助于无声清除。这些研究将在体外使用select
分离的补体成分,以及在体内使用独特的C1 q和C3缺陷小鼠。
结果测量包括吞噬作用、细胞因子产生和NET形成。
参与尿道介导的炎症的下游信号通路将被
使用基于质谱的磷酸化蛋白质组学鉴定。总之,我们的研究旨在
确定调节炎症、血栓形成和自身免疫的基本机制,
在人类疾病的背景下,强调补体系统在沉默中的作用,
去除线粒体。我们希望拟议的研究提供新的治疗靶点
破坏线粒体的炎症和免疫原性,适用于许多
疾病,包括SLE和类风湿性关节炎,以及确定预后线粒体-
衍生的生物标志物能够早期和预防性治疗静脉血栓形成。
项目成果
期刊论文数量(0)
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Jan Christian Lood其他文献
Jan Christian Lood的其他文献
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{{ truncateString('Jan Christian Lood', 18)}}的其他基金
Role of mitochondria in SLE and its cardiovascular complications
线粒体在 SLE 及其心血管并发症中的作用
- 批准号:
10473713 - 财政年份:2021
- 资助金额:
$ 60.89万 - 项目类别:
Extracellular mitochondria in Inclusion Body Myositis
包涵体肌炎的细胞外线粒体
- 批准号:
10282390 - 财政年份:2021
- 资助金额:
$ 60.89万 - 项目类别:
Role of mitochondria in SLE and its cardiovascular complications
线粒体在 SLE 及其心血管并发症中的作用
- 批准号:
10652483 - 财政年份:2021
- 资助金额:
$ 60.89万 - 项目类别:
Mitochondrial calcification in juvenile dermatomyositis
幼年皮肌炎的线粒体钙化
- 批准号:
10245228 - 财政年份:2020
- 资助金额:
$ 60.89万 - 项目类别:
Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis
研究血小板衍生生长因子受体如何指导炎症关节炎中滑膜成纤维细胞介导的病理学
- 批准号:
10260607 - 财政年份:2020
- 资助金额:
$ 60.89万 - 项目类别:
Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis
研究血小板衍生生长因子受体如何指导炎症关节炎中滑膜成纤维细胞介导的病理学
- 批准号:
10247966 - 财政年份:2020
- 资助金额:
$ 60.89万 - 项目类别:
Mitochondrial calcification in juvenile dermatomyositis
幼年皮肌炎的线粒体钙化
- 批准号:
10027222 - 财政年份:2020
- 资助金额:
$ 60.89万 - 项目类别:
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