Project-005
Project-005
批准号:
10227919
负责人:
Lei Li
金额:
$27.49万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-05-01 至 2023-04-30
关键词:
AntibodiesAntibody FormationAntigen-Presenting CellsAntigensB-LymphocytesBacteriaBindingBlood coagulationBypassCaringCellsClinical TreatmentComplexComplicationData AnalysesDevelopmentEngineeringEnvironmentEnvironmental Risk FactorEpitopesEventExhibitsF8 geneFaceFactor VIIIFrequenciesGene ExpressionGenesGeneticGenetic RiskGlycobiologyGlycopeptidesGlycoproteinsHemophilia AHemorrhageHumanImmuneImmune ToleranceImmune responseImmune systemImmunologicsImmunologyInfrastructureInvestigationLateralLeadMass Spectrum AnalysisMediatingMicroarray AnalysisMorbidity - disease rateMouse StrainsMusMutationOligosaccharidesOrganPathway interactionsPatientsPatternPeptide HydrolasesPhysiciansPolysaccharidesPreventionProtein GlycosylationProteinsQuality of lifeRegimenReplacement TherapyResearchResearch PersonnelResearch Project GrantsRiskRoleServicesSeveritiesSignal TransductionSpecificitySurveysT-LymphocyteTCR ActivationTechnologyTissuesTrainingTraining and EducationVariantVirusadaptive immune responseantibody inhibitorbasecell growth regulationcostenzyme replacement therapygene therapyglycoproteomicsglycosylationimmune activationimmunoregulationinhibitor/antagonistinnovationinnovative technologiesinsightmultidisciplinarynovelpatient subsetsprotein expressionprotein protein interactionresponseskillsstudent trainingtheoriestrafficking
中文摘要
治疗血友病A的一个主要障碍是约25%的患者产生高滴度、中和的抗第VIII因子
(Fviii)蛋白质替代疗法后的抗体(抑制物)。预计这一问题还将
在至少一部分患者中,在基因治疗后发生。治疗血友病尤其具有挑战性。
已经产生抑制性抗体的患者。绕过用来治疗这些患者的疗法
有时疗效有限,而且成本很高。抗FVIII抑制抗体的形成是由
涉及遗传和环境风险因素的复杂的多方面免疫反应。几个“危险”
信号“已被证明与抑制剂形成的风险有关。然而,潜在的
激活抗FVIII反应的触发因素尚不完全清楚。例如,具有相同突变的患者
在蛋白质替代治疗后,FVIII基因在抑制物的发展中具有不同的风险。此外,
有一些迹象表明,不同的FVIII产品可能表现出不同程度的抑制剂风险。在最近
多年来,已经证明多糖对免疫系统至关重要,因为其中一些最重要的
免疫系统与病毒或细菌或外源添加的蛋白质之间的相互作用是由
通过蛋白质-糖链的相互作用。糖基化几乎参与了免疫激活途径的每一步。
糖链是识别非我事件的关键,糖链的改变可以导致免疫的激活
回应。糖基化也参与了控制TCR激活阈值的细胞机制,
免疫细胞运输、TCR和BCR信号、抗体功能等。我们假设这一影响
葡聚糖在诱导免疫反应或对FVIII的耐受方面可以有两个方面:一是相互作用
糖基化的FVIII抗原和具有特定糖链特征的宿主免疫系统在
确定诱导抗FVIII免疫反应的风险;第二是对FVIII的识别和随后
通过外源添加的蛋白质或基因表达而激活的免疫可以不同程度地改变或
FVIII糖类的花纹。因此,为了更全面地了解潜在糖基化的光谱
影响抗FVIII抑制反应的发展,我们建议首先看看宿主的影响
不同背景的人和小鼠在抗FVIII反应发展过程中的葡聚糖谱。
接下来,我们将表征不同程度或不同程度的FVIII分子的传递所引起的免疫反应
糖基化模式,并探讨其免疫激活机制。从这项研究中,我们希望定义
糖基化引起的特异性免疫触发及其相关机制,导致预防或消除
一种FVIII抑制剂。
英文摘要
A major obstacle in treating hemophilia A is that ~25% of patients develop high-titer, neutralizing anti-factor VIII
(FVIII) antibodies (inhibitors) following protein replacement therapy. It is also anticipated that this problem will
occur following gene therapy in at least a subset of patients. It is particularly challenging to treat hemophilia
patients who have developed inhibitory antibodies. Bypassing therapies that are used to treat these patients
sometimes have limited efficacy and are very costly. The anti-FVIII inhibitory antibody formation results from a
complex multifaceted immune response involving both genetic and environmental risk factors. Several “danger
signals” have been demonstrated to be associated with risks of inhibitor formation. However, the potential
triggers to activate anti-FVIII responses are not fully understood. For example, patients with identical mutations
in FVIII gene can have differential risks in inhibitor development following protein replacement therapy. Moreover,
there were some implications that different FVIII products may exhibit different degrees of inhibitor risks. In recent
years, it has been demonstrated that glycans are crucial for the immune system, as some of the most important
interactions between the immune system and viruses or bacteria or exogenously added proteins are mediated
by protein-glycan interactions. Glycosylation is involved in almost every step of the immune activation pathway.
Glycans are a key in the recognition of non-self events and an altered glycome can lead to activation of immune
responses. Glycosylation is also involved in the cellular mechanisms that control the threshold of TCR activation,
immune cell trafficking, TCR and BCR signaling, antibody function, and more. We hypothesize that the impact
of glycans in the induction of immune response or tolerance to FVIII can be two-fold: one is that the interaction
of glycosylated FVIII antigens and host immune system with specific glycan profiles can be significant in
determining the risk of inducing anti-FVIII immune response; and the second is that the recognition of and ensued
immune activation by exogenously added protein or gene expression can be altered by different extent or
patterns of FVIII glycomes. Therefore, in order to more fully understand the spectrum of potential glycosylation
influence on the development of anti-FVIII inhibitor responses, we propose to first look into the influence of host
glycan profiles in the development of anti-FVIII response both in humans and mice with different backgrounds.
Next we will characterize the immune responses elicited by delivery of FVIII molecules with different extent or
patterns of glycosylation and investigate the mechanism of immune activation. From this study, we wish to define
specific immunologic trigger by glycosylation and its associated mechanisms, leading to prevention or elimination
of FVIII inhibitors.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Expedite Enzymatic Assembly of Glycans via DNA (de)Hybridization-Enabled Catch-and-Release
-
批准号:10648697
-
项目类别:
-
资助金额:$23.4万
-
财政年份:2023
-
负责人:Lei Li
-
依托单位:
Project-004
-
批准号:10406321
-
项目类别:
-
资助金额:$25.82万
-
财政年份:2018
-
负责人:Lei Li
-
依托单位:
Center for the Investigation of Factor VIII Inhibitors and Glycosylation
-
批准号:10406318
-
项目类别:
-
资助金额:$132.38万
-
财政年份:2018
-
负责人:Lei Li
-
依托单位:
Project-004
-
批准号:10227918
-
项目类别:
-
资助金额:$26.09万
-
财政年份:2018
-
负责人:Lei Li
-
依托单位:
Project-005
-
批准号:10406322
-
项目类别:
-
资助金额:$27.08万
-
财政年份:2018
-
负责人:Lei Li
-
依托单位:
Center for the Investigation of Factor VIII Inhibitors and Glycosylation
-
批准号:10227911
-
项目类别:
-
资助金额:$134.67万
-
财政年份:2018
-
负责人:Lei Li
-
依托单位:
A Comprehensive 5K Plus Glycan Microarray
-
批准号:10557232
-
项目类别:
-
资助金额:$45.4万
-
财政年份:2017
-
负责人:Lei Li
-
依托单位:
A Comprehensive 5K Plus Glycan Microarray
-
批准号:10353411
-
项目类别:
-
资助金额:$51.92万
-
财政年份:2017
-
负责人:Lei Li
-
依托单位:
Facile Synthesis of O-Glycans and O-Glycopeptides
-
批准号:8985647
-
项目类别:
-
资助金额:$49.3万
-
财政年份:2015
-
负责人:Lei Li
-
依托单位:
Battling AIDS via Mechanistic Understanding of the tRNA Phe modification enzyme T
-
批准号:8229462
-
项目类别:
-
资助金额:$22.93万
-
财政年份:2012
-
负责人:Lei Li
-
依托单位:
Battling AIDS via Mechanistic Understanding of the tRNA Phe modification enzyme T
-
批准号:8514508
-
项目类别:
-
资助金额:$17.87万
-
财政年份:2012
-
负责人:Lei Li
-
依托单位:
Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
-
批准号:7923993
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2009
-
负责人:Lei Li
-
依托单位:
Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
-
批准号:7881168
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2009
-
负责人:Lei Li
-
依托单位:
Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
-
批准号:8117523
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2009
-
负责人:Lei Li
-
依托单位:
Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
-
批准号:7449890
-
项目类别:
-
资助金额:$8.26万
-
财政年份:2008
-
负责人:Lei Li
-
依托单位:
Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
-
批准号:7620392
-
项目类别:
-
资助金额:$8.44万
-
财政年份:2008
-
负责人:Lei Li
-
依托单位:
海外基金