权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Exploring the mechanisms of action of anti-ADAMTS 13 antibodies in immune thrombotic thrombocytopenic purpura

探讨抗 ADAMTS 13 抗体在免疫性血栓性血小板减少性紫癜中的作用机制

基本信息

批准号：
10685963
负责人：
Konstantine Halkidis
金额：
$ 16.52万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2022-08-18 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685963
关键词：
Advisory Committees Affect Affinity Agglutination Agreement Antibodies Area Autoantibodies Autoimmune Binding Binding Sites Biological Assay Blood Platelets Blood Vessels Cell Therapy Clinic Clinical Clinical Management Coupled Data Deuterium Development Plans Diagnostic Diagnostic tests Disease Disease Management Disintegrins Distal Endothelium Enzyme Inhibition Enzymes Epitopes Functional disorder Goals Hematologic Neoplasms Hematological Disease Human Hydrogen IgG autoantibodies Immune Immunodiagnostics Immunoglobulin G Immunotherapy Individual Informal Social Control Internal Medicine Kansas Life Mass Spectrum Analysis Mediating Medical center Mentors Metalloproteases Molecular Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Non-Neoplastic Hematologic and Lymphocytic Disorder Organ Outcome Pathogenesis Patients Phage Display Physicians Physiological Plasma Plasmapheresis Process Prognosis Recurrent disease Research Research Personnel Role Scientist Site Source Specificity Structure Techniques Temperature Tertiary Protein Structure Testing Therapeutic Agents Therapeutic Intervention Thrombosis Thrombospondins Thrombotic Thrombocytopenic Purpura Time Training Translating Universities Work career career development cleavage factor disorder risk enzyme activity human monoclonal antibodies improved in vitro activity in vivo in-vitro diagnostics inhibiting antibody inhibitor insight meetings mortality novel diagnostics novel strategies novel therapeutic intervention prevent professor structural biology tenure track thrombotic von Willebrand Factor

项目摘要

Project Summary/Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by autoimmune inhibition of the enzyme ADAMTS13. The only known substrate of ADAMTS13 is von Willebrand factor (VWF). Cleavage of VWF by ADAMTS13 is needed to prevent accumulation of ultralarge VWF multimers in the microvasculature, leading to end-organ damage and potentially life-threatening consequences. Anti-ADAMTS13 IgGs are responsible for the inhibition of the enzyme. The vast majority of inhibitory antibodies target a region of ADAMTS13 that is principally responsible for binding to the domain of VWF cleaved by the enzyme. However, the mechanism of inhibition of these antibodies is currently an area of active research, and it is not known if they primarily prevent substrate binding or decrease catalytic turnover, or if different antibodies inhibit by different mechanisms. Recent work has shown that ADAMTS13 in iTTP patient plasma exists primarily in a conformation that exposes a cryptic epitope otherwise hidden when ADAMTS13 is in its latent state. The current paradigm of ADAMTS13 activity defines this as a so-called “Open” state, and the latent state as “Closed”. A third state also appears to exist in which ADAMTS13 has the cryptic episode exposed, but also is able to cleave VWF; this is referred to here as the “Open and Primed” state. Anti-ADAMTS13 IgGs that target distal domains of the protein appear capable of inducing both the “Open” and “Open and Primed” state. The role of the different conformations of ADAMTS13 in the pathophysiology of iTTP is unclear, as is the potential role of the distal domain-targeting IgGs in the disease. Lastly, it is not known if ADAMTS13 activity can be rescued by introducing moieties capable of competing for the binding of anti-ADAMTS13 IgGs with ADAMTS13. This project aims to elucidate the mechanism(s) of inhibition of anti-ADAMTS13 antibodies, characterize the role of distal domain-targeting anti- ADAMTS13 antibodies in the pathophysiology of the disease, and explore molecular mimics of the binding epitopes of anti-ADAMTS13 IgGs as a rescue strategy for the disease. My career goal is to become an independent investigator as a physician scientist, with a focus on the pathophysiology of iTTP. I am currently on the tenure-track as an Assistant Professor in the Department of Internal Medicine, Division of Hematologic Malignancies and Cellular Therapeutics, at the University of Kansas Medical Center (KUMC), a large academic center. My research mentor is Dr. X. Long Zheng, a world-renowned researcher in iTTP. I am afforded 80% protected time for research under my agreement with the University. My career development plan includes regular meetings with my Career Advisory Committee, hands-on training in the structural biology techniques included in this proposal, and ongoing clinical responsibilities, including a half-day of clinic weekly where I see patients with non-malignant hematologic disorders.

项目概要/摘要 Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by autoimmune 抑制 ADAMTS13 酶。 ADAMTS13 唯一已知的底物是血管性血友病因子 (VWF)。需要通过 ADAMTS13 切割 VWF，以防止超大型 VWF 多聚体在微血管，导致终末器官损伤并可能危及生命。抗 ADAMTS13 IgG 负责抑制酶。绝大多数抑制性抗体靶向以下区域 ADAMTS13 主要负责与酶切割的 VWF 结构域结合。然而，这些抗体的抑制机制目前是一个活跃的研究领域，尚不清楚它们是否有效主要防止底物结合或减少催化周转，或者如果不同的抗体通过不同的抑制机制。最近的工作表明 iTTP 患者血浆中的 ADAMTS13 主要以构象存在当 ADAMTS13 处于潜伏状态时，它会暴露一个隐藏的表位。目前的范式 ADAMTS13 活动将此定义为所谓的“打开”状态，将潜在状态定义为“关闭”。还有第三种状态似乎存在 ADAMTS13 暴露了神秘事件，但也能够裂解 VWF；这是这里称为“打开并准备好”状态。靶向蛋白质远端结构域的抗 ADAMTS13 IgG 似乎能够诱导“开放”和“开放和准备”状态。不同构象的作用 ADAMTS13 在 iTTP 病理生理学中的作用尚不清楚，远端结构域靶向的潜在作用也不清楚疾病中存在 IgG。最后，尚不清楚 ADAMTS13 活性是否可以通过引入具有能力的部分来挽救竞争抗 ADAMTS13 IgG 与 ADAMTS13 的结合。该项目旨在阐明抑制抗 ADAMTS13 抗体的机制，表征远端域靶向抗-ADAMTS13 抗体的作用 ADAMTS13 抗体在疾病病理生理学中的作用，并探索结合的分子模拟物抗 ADAMTS13 IgG 的表位作为该疾病的救援策略。我的职业目标是成为作为一名医学科学家的独立研究者，重点研究 iTTP 的病理生理学。我目前正在内科血液学系助理教授的终身职位大型学术机构堪萨斯大学医学中心 (KUMC) 的恶性肿瘤和细胞治疗中心。我的研究导师是世界著名iTTP研究员郑X龙博士。我负担80% 根据我与大学的协议，受保护的研究时间。我的职业发展计划包括与我的职业咨询委员会定期举行会议，进行结构生物学技术的实践培训包括在这个提案中，以及持续的临床责任，包括每周半天的诊所，我在那里看到患有非恶性血液系统疾病的患者。