Mechanistic insights into factor VIII inhibitor formation and eradication
对因子 VIII 抑制剂形成和根除的机制见解
基本信息
- 批准号:10641791
- 负责人:
- 金额:$ 15.52万
- 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:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAdvisory CommitteesAffinityAnimal ModelAntibodiesAntibody ResponseAntibody TherapyAntigensAutoimmune DiseasesAwardB-Cell ActivationB-Lymphocyte SubsetsB-LymphocytesBasic ScienceBeta CellBiological MarkersBloodBlood Coagulation DisordersBypassCD4 Positive T LymphocytesCareer ChoiceCell MaturationCellsCementationChronicClinicCoagulation Factor DeficiencyCoagulation ProcessCytokine GeneDataDendritic CellsDependenceDevelopmentDiseaseDoseEducational workshopEquilibriumF8 geneFactor VIIIFibroblastsFosteringFunctional disorderFutureGenerationsGeneticGenetic PolymorphismGenomicsGenotypeGoalsHelper-Inducer T-LymphocyteHematological DiseaseHematopoieticHemophilia AHemorrhageHemostatic functionHomeostasisHumanImmuneImmune ToleranceImmune responseImmunizationImmunizeImmunoglobulin Somatic HypermutationImmunologicsImmunologyIn VitroInfusion proceduresInheritedInterleukin-10InvestigationIsoantibodiesJointsKineticsLearningLicensingLocationMS4A1 geneMarrowMature B-LymphocyteMemoryMemory B-LymphocyteMentorsMethodsMorbidity - disease rateMusMutationPathogenesisPatientsPersonsPharmaceutical PreparationsPhenotypePhysiciansPlasma CellsPopulationPredisposing FactorPrevention strategyProliferatingQuality of lifeResearchResearch ProposalsRoleSamplingScienceScientistSecondary toSeriesSourceStructure of germinal center of lymph nodeSusceptibility GeneT cell responseT-LymphocyteTNF geneTherapeuticTrainingTraining ProgramsTranslatingTranslational ResearchVariantWorkanti-CD20arthropathiesbelimumabbiobankcareercareer developmentcytokineenzyme replacement therapyexperiencehands on researchimmunogenicityimmunomodulatory strategyimmunomodulatory therapiesimprovedin vivoinhibitorinhibitor therapyinsightmembermigrationmortalitymouse modelneutralizing antibodynovelnovel markerpre-clinicalpredictive markerpreventrecruitresponsesecondary lymphoid organskillstargeted treatmenttissue culturetranslational physiciantreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
This K99 Career Pathway to Independence in Blood Science Award details a five-year training program to
advance Dr. Bhavya Doshi’s career goal of becoming an independent translational physician-scientist in
coagulation. The proposed application combines approaches using tissue culture and animal models with
investigations using patient samples to address the current limitations in the understanding of the immune
response to factor VIII (FVIII). Dr. Doshi’s career development and training objectives are geared to foster this
research proposal and her overall career goal of understanding basic mechanisms that drive disease to
develop targeted treatment and prevention strategies. During the award period, Dr. Doshi will engage with a
robust team of scientists in hemostasis and immunology to build her immunologic and translational research
skills, learn genomic skills necessary for her future career aspirations, and continue to develop her expertise in
coagulation and inhibitors. Under the guidance of her mentors, Dr. Rodney Camire and Dr. Michael Milone,
these training objectives will be met by a combination of didactic course work and workshops, participation in
seminar series, hands-on research experience, and mentoring by her advisory committee. Her advisory
committee is composed of world-renowned scientists with extensive mentoring experience and diverse and
complementary scientific expertise. They are all versed in bringing basic research findings to the bedside.
Hemophilia A (HA) is caused by a mutation in the F8 gene leading to dysfunction or deficiency of coagulation
FVIII. The development of neutralizing antibodies (“inhibitors”) to FVIII is the leading cause of morbidity and
mortality in patients with HA. Dr. Doshi’s preliminary studies in HA patients and mice are the first to support
that the cytokine B cell activating factor (BAFF) is potentially a biomarker and/or regulator of the FVIII immune
response. This proposal seeks to probe basic mechanisms in FVIII-specific B cell generation and how BAFF
contributes to this humoral response in order to leverage these findings for therapeutic application. Aim 1
seeks to determine the location, kinetics, and types of B cell responses to FVIII in mice by using a novel
method to identify FVIII-specific B cells and subsequently determine what happens to this compartment with
immunomodulatory strategies, including anti-BAFF. As BAFF is both systemically and locally produced by
fibroblast cells and hematopoietically-derived immune cells, respectively, Aim 2 investigates the source of
BAFF and its effect on the T cell response to FVIII. Finally, Aim 3 assesses whether genetic drivers of cytokine
levels for BAFF or T helper cytokines drive phenotypic changes in T and B cell subsets that lead to inhibitor
generation and/or persistence in HA patients. Together, these studies will inform the immune compartments
that are critical to the FVIII immune response and establish the preclinical data to translate anti-BAFF therapy
to the clinics. The research and career objectives in this proposal will bolster Dr. Doshi’s research repertoire to
enable her transition to an independent physician scientist focused on blood disorders, specifically hemophilia.
项目概要/摘要
K99 血液科学独立职业之路奖详细介绍了一个为期五年的培训计划
推进 Bhavya Doshi 博士成为独立转化医学科学家的职业目标
凝固。拟议的应用程序将使用组织培养和动物模型的方法与
使用患者样本进行研究以解决当前免疫理解的局限性
对因子 VIII (FVIII) 的反应。多西博士的职业发展和培训目标旨在促进这一点
研究提案和她了解导致疾病的基本机制的总体职业目标
制定有针对性的治疗和预防策略。在颁奖期间,多西博士将与
强大的止血和免疫学科学家团队致力于建立她的免疫学和转化研究
技能,学习她未来职业抱负所需的基因组技能,并继续发展她的专业知识
凝血和抑制剂。在她的导师 Rodney Camire 博士和 Michael Milone 博士的指导下,
这些培训目标将通过教学课程和讲习班、参与
研讨会系列、实践研究经验以及咨询委员会的指导。她的咨询
委员会由具有丰富指导经验和多元化的世界知名科学家组成
互补的科学专业知识。他们都擅长将基础研究成果带到临床。
A 型血友病 (HA) 是由 F8 基因突变导致凝血功能障碍或缺陷引起的
FVIII. FVIII 中和抗体(“抑制剂”)的产生是发病和死亡的主要原因
HA 患者的死亡率。 Doshi 博士对 HA 患者和小鼠进行的初步研究首次支持
细胞因子 B 细胞激活因子 (BAFF) 可能是 FVIII 免疫的生物标志物和/或调节因子
回复。该提案旨在探讨 FVIII 特异性 B 细胞生成的基本机制以及 BAFF 如何
有助于这种体液反应,以便利用这些发现进行治疗应用。目标1
试图通过使用一种新的方法来确定小鼠 B 细胞对 FVIII 反应的位置、动力学和类型
识别 FVIII 特异性 B 细胞并随后确定该区室发生情况的方法
免疫调节策略,包括抗 BAFF。由于 BAFF 是由系统和本地生产的
分别是成纤维细胞和造血来源的免疫细胞,目标 2 研究了
BAFF 及其对 T 细胞对 FVIII 反应的影响。最后,目标 3 评估细胞因子的遗传驱动因素是否
BAFF 或 T 辅助细胞因子的水平驱动 T 和 B 细胞亚群的表型变化,从而导致抑制剂
HA 患者中的产生和/或持续。这些研究共同将为免疫区室提供信息
对 FVIII 免疫反应至关重要,并建立临床前数据以转化抗 BAFF 疗法
到诊所。该提案中的研究和职业目标将增强多西博士的研究能力
使她能够转变为一名专注于血液疾病,特别是血友病的独立医师科学家。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Acquired Hemophilia A: Current Guidance and Experience from Clinical Practice.
- DOI:10.2147/jbm.s284804
- 发表时间:2022
- 期刊:
- 影响因子:2
- 作者:
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Bhavya Sharad Doshi其他文献
Bhavya Sharad Doshi的其他文献
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{{ truncateString('Bhavya Sharad Doshi', 18)}}的其他基金
Mechanistic insights into factor VIII inhibitor formation and eradication
对因子 VIII 抑制剂形成和根除的机制见解
- 批准号:
10413819 - 财政年份:2021
- 资助金额:
$ 15.52万 - 项目类别:
Mechanistic insights into factor VIII inhibitor formation and eradication
对因子 VIII 抑制剂形成和根除的机制见解
- 批准号:
10117521 - 财政年份:2021
- 资助金额:
$ 15.52万 - 项目类别:
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