Structure-based Design of Rational PF4 Inhibitors in HIT
HIT 中合理 PF4 抑制剂的基于结构的设计
基本信息
- 批准号:9900853
- 负责人:
- 金额:$ 57.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesAntibody AvidityAnticoagulant therapyAnticoagulantsAnticoagulationAntidotesAntigen-Antibody ComplexAntigensAntithrombin IIIAutoimmune ProcessBindingBiochemicalBiological AssayBiophysicsBypassCRISPR/Cas technologyCardiacCardiovascular Surgical ProceduresCellsClinical ResearchComplementComplexCrystallizationDetectionDiagnosisDiagnosticDiseaseEnzyme-Linked Immunosorbent AssayExposure toGenerationsHemorrhageHemostatic AgentsHeparinHeparin BindingHumanIn VitroInterruptionInterventionKnock-in MouseLeadMediatingMonoclonal AntibodiesMusOperative Surgical ProceduresPF4 GenePathogenesisPathogenicityPathway interactionsPatientsPharmaceutical PreparationsPhysiologicalPlasmaPlatelet ActivationPredictive Value of TestsPrevalencePropertyRecurrenceRiskRoleSafetySamplingStructureSymptomsTestingTherapeuticThrombocytopeniaThromboplastinThrombosisTransgenic OrganismsVariantbasebiophysical analysisbiophysical techniquesclinical Diagnosisclinically relevantcofactordesignexperimental studyheparin cofactorheparin-induced thrombocytopenia high riskin vivoinhibiting antibodyinhibitor/antagonistmonocytemonomermouse modelmutantnovelnovel diagnosticspolyanionpreservationpreventreceptortool
项目摘要
ABSTRACT
Heparin-induced thrombocytopenia (HIT) is thrombotic disorder caused by immune complexes that develops in
settings where unfractionated heparin (UFH) remains the standard anticoagulant. For those with thrombotic
complications, alternative anticoagulants do not mitigate symptoms, provide only partial protection against
recurrent thrombosis and carry a risk of bleeding for which there is no antidote. HIT is over-diagnosed because
current assays do not distinguish pathogenic from non-pathogenic anti-PF4 antibodies (Abs). There is need for
better understanding the pathogenesis of HIT to develop better diagnostics and rational, disease-specific, non-
anticoagulant management. We recently described the crystal structure of PF4 in complex with a heparin-
based pentamer and a HIT-like murine (m) Ab (KKO). We showed that an anti-PF4 mAb (RTO) that prevents
PF4 from forming tetramers and higher-ordered immune complexes, prevents platelet activation by HIT Abs in
vitro, and thrombocytopenia and thrombosis caused by HIT Abs in vivo. Based on these structures, we
developed Class I PF4 monomeric mutants that are unable to form tetramers, and thereby inhibit propagation
of oligomeric PF4/UFH complexes that bind KKO and human HIT Abs, activate FcRγIIA receptors, inhibit
expression of tissue factor and cause less inhibition of UFH/antithrombin III cofactor activity than native PF4.
We also developed Class II PF4 mutants that form antigen-negative tetramers as an alternative approach. In
this proposal, we will analyze these two classes of PF4 variants to better understand the pathogenesis of HIT
and to develop novel diagnostic and potential therapeutic tools. Specific Aims (SA)#1. Efficacy, safety,
mechanism of action and structure of Class I and II PF4 mutants. These studies will examine how PF4,
heparin and HIT Abs oligomerize to form higher-ordered antigenic complexes. We will determine whether
these PF4 variants block immune complex formation in vitro and in a murine model of HIT while generating a
favorable hemostatic profile in this thrombotic disease. SA#2. Generation and characterization of Class I
human and mouse PF4 mice. In vivo studies will be extended using CRISPR/Cas9 technology to develop
mice expressing Class I monomeric PF4 variants and to examine their effects in a murine model of HIT. SA#3.
Utility of Class I monomeric PF4 variants to distinguish pathogenic from non-pathogenic HIT Abs.
Class I PF4 monomer columns will be used to separate pathogenic HIT Abs that bind tetrameric PF4/polyanion
complexes from non-pathogenic Abs that bind monomeric PF4 and block binding of pathogenic Abs. We will
test a novel hypothesis that HIT is more prevalent in patients lacking such blocking Abs. Together the
proposed studies combine biophysical studies, novel murine models and a new hypothesis involving human
samples that will provide a better understanding of immune complex formation in HIT, develop a disease-
specific ELISA, and potentially offer a basis for a rational non-anticoagulant approach to complement
contemporary anti-thrombotic therapy to mitigate this serious autoimmune thrombotic disorder.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Douglas Brock Cines其他文献
Douglas Brock Cines的其他文献
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{{ truncateString('Douglas Brock Cines', 18)}}的其他基金
Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3
集合管 α-防御素 1-3 的遗传调控、管状加工和临床相关性
- 批准号:
9906213 - 财政年份:2018
- 资助金额:
$ 57.22万 - 项目类别:
Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3
集合管 α-防御素 1-3 的遗传调控、管状加工和临床相关性
- 批准号:
10133060 - 财政年份:2018
- 资助金额:
$ 57.22万 - 项目类别:
Prevention and management of perioperative pulmonary embolism
围手术期肺栓塞的预防和处理
- 批准号:
8421570 - 财政年份:2013
- 资助金额:
$ 57.22万 - 项目类别:
Prevention and management of perioperative pulmonary embolism
围手术期肺栓塞的预防和处理
- 批准号:
8723275 - 财政年份:2013
- 资助金额:
$ 57.22万 - 项目类别:
Nuclear translocation of urokinase/nucleolin complexes
尿激酶/核仁素复合物的核转位
- 批准号:
7319578 - 财政年份:2007
- 资助金额:
$ 57.22万 - 项目类别:
Nuclear translocation of urokinase/nucleolin complexes
尿激酶/核仁素复合物的核转位
- 批准号:
7483764 - 财政年份:2007
- 资助金额:
$ 57.22万 - 项目类别:
UROKINASE KRINGLE-MEDIATED VASCULAR REMODELING
尿激酶Kringle介导的血管重塑
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6288389 - 财政年份:2001
- 资助金额:
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