Structural analysis of the HIT immune complex

HIT 免疫复合物的结构分析

• 批准号: 8945196
• 负责人: Zheng Cai
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945196
• 关键词: Adhesions; Antibodies; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoimmune Diseases; Binding; Blood Platelets; Cells; Cessation of life; Clinical; Clinical Research; Collagen; Complex; Data; Development; Diagnosis; Diagnostic Procedure; Disease; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epitopes; Fc Receptor; Future; Generations; Glycosaminoglycans; Hemostatic Agents; Heparin; Human; IgG4; Immune response; In Vitro; Individual; Knowledge; Laser injury; Lead; Link; Low-Molecular-Weight Heparin; Measures; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Pathogenesis; Patients; Platelet Activation; Platelet Factor 4; Pre-Clinical Model; Preparation; Prevalence; Process; Proteins; Recurrence; Risk; Serological; Solutions; Structural Models; Structure; Surface; System; Testing; Therapeutic; Thrombin; Thrombocytopenia; Thromboembolism; Thrombosis; Venous Thrombosis; base; dimer; fondaparinux; humanized antibody; improved; in vivo Model; limb amputation; monocyte; monomer; mutant; novel; novel diagnostics; prevent; public health relevance

 DESCRIPTION (provided by applicant): HIT is a severe autoimmune disorder that predisposes to arterial and venous thrombosis. HIT is notable for several reasons, including the remarkable prevalence of otherwise immunologically healthy individuals exposed to heparin who develop self-reactive antibodies to a normal host protein, PF4, when it is released following platelet activation. Current clinical challenges in HIT include over-diagnosis and over-treatment and well as the risks of anticoagulating patients with thrombocytopenia and other hemostatic challenges such as recent surgery. In this proposed study, we will try to obtain in-depth understanding of the pathogenic ternary complex using crystallographic studies. We will try to expand our understanding of the PF4 tetramerization process and the creation of a novel type of antigenic epitope. We will try to develop a panel of PF4 mutants in different states of oligomerization that may provide a more reliable diagnostic method. We will also humanize RTO, maintain its PF4-monomer binding ability, but minimize the human immune response in preparation for potential future clinical studies.

 描述（由申请人提供）：HIT是一种严重的自身免疫性疾病，易发生动脉和静脉血栓形成。HIT值得注意的原因有几个，包括暴露于肝素的其他免疫健康个体的显著流行，这些个体在血小板活化后释放正常宿主蛋白PF 4时产生自身反应性抗体。HIT目前的临床挑战包括过度诊断和过度治疗，以及抗血小板患者血小板减少和其他止血挑战（如近期手术）的风险。在这项拟议的研究中，我们将尝试使用晶体学研究来深入了解致病性三元复合物。我们将试图扩大我们的理解PF 4四聚体的过程和创造一种新型的抗原表位。我们将尝试开发一组不同寡聚化状态的PF 4突变体，这可能提供更可靠的诊断方法。我们还将人源化RTO，保持其PF 4-单体结合能力，但最大限度地减少人体免疫反应，为未来潜在的临床研究做准备。