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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：
Bhavya Sharad Doshi
金额：
$ 15.52万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
https://reporter.nih.gov/project-details/10641791
关键词：
Acquired Immunodeficiency Syndrome Address Advisory Committees Affinity Animal Model Antibodies Antibody Response Antibody Therapy Antigens Autoimmune Diseases Award B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Basic Science Beta Cell Biological Markers Blood Blood Coagulation Disorders Bypass CD4 Positive T Lymphocytes Career Choice Cell Maturation Cells Cementation Chronic Clinic Coagulation Factor Deficiency Coagulation Process Cytokine Gene Data Dendritic Cells Dependence Development Disease Dose Educational workshop Equilibrium F8 gene Factor VIII Fibroblasts Fostering Functional disorder Future Generations Genetic Genetic Polymorphism Genomics Genotype Goals Helper-Inducer T-Lymphocyte Hematological Disease Hematopoietic Hemophilia A Hemorrhage Hemostatic function Homeostasis Human Immune Immune Tolerance Immune response Immunization Immunize Immunoglobulin Somatic Hypermutation Immunologics Immunology In Vitro Infusion procedures Inherited Interleukin-10 Investigation Isoantibodies Joints Kinetics Learning Licensing Location MS4A1 gene Marrow Mature B-Lymphocyte Memory Memory B-Lymphocyte Mentors Methods Morbidity - disease rate Mus Mutation Pathogenesis Patients Persons Pharmaceutical Preparations Phenotype Physicians Plasma Cells Population Predisposing Factor Prevention strategy Proliferating Quality of life Research Research Proposals Role Sampling Science Scientist Secondary to Series Source Structure of germinal center of lymph node Susceptibility Gene T cell response T-Lymphocyte TNF gene Therapeutic Training Training Programs Translating Translational Research Variant Work anti-CD20 arthropathies belimumab biobank career career development cytokine enzyme replacement therapy experience hands on research immunogenicity immunomodulatory strategy immunomodulatory therapies improved in vivo inhibitor inhibitor therapy insight member migration mortality mouse model neutralizing antibody novel novel marker pre-clinical predictive marker prevent recruit response secondary lymphoid organ skills targeted treatment tissue culture translational physician treatment 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。