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.

项目摘要/摘要这项K99血液科学独立奖的职业途径详细介绍了一项为期五年的培训计划促进Bhavya Doshi博士的职业目标是成为独立翻译的身体科学家凝血。提出的应用使用组织培养和动物模型与使用患者样品的调查以解决理解免疫的当前局限性对因子VIII（FVIII）的响应。 Doshi博士的职业发展和培训目标旨在促进此事研究提案及其整体职业目标是理解推动疾病的基本机制制定有针对性的治疗和预防策略。在颁奖期间，多希博士将与强大的止血和免疫学科学家团队建立免疫学和转化研究技能，学习未来职业愿望所需的基因组技能，并继续发展她的专业知识凝结和抑制剂。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的结合来实现她的咨询委员会的开创性系列，动手研究经验和心理。她的咨询委员会由拥有丰富心理经验和多样化的世界知名科学家组成，完全科学专业知识。他们都精通将基础研究发现带到床边。血友病A（HA）是由F8基因突变引起的，导致功能障碍或凝结功能不足 FVIII。对FVIII中和抗体的发展是发病率和的主要原因 HA患者的死亡率。 Doshi博士对HA患者和小鼠的初步研究是第一个支持细胞因子B细胞激活因子（BAFF）可能是FVIII免疫的生物标志物和/或调节剂回复。该提案旨在探究FVIII特异性B细胞产生的基本机制以及如何BAFF 为了将这些发现用于治疗应用，有助于这种体液反应。目标1 试图通过使用新颖识别FVIII特异性B细胞并随后确定此隔室的方法免疫调节策略，包括抗BAFF。由于Baff是系统地和本地生产的成纤维细胞和造血衍生的免疫细胞的目标2研究了 BAFF及其对T细胞对FVIII的影响的影响。最后，AIM 3评估是否是细胞因子的遗传驱动因素 BAFF或T辅助细胞因子的水平驱动T和B细胞子集的表型变化，导致抑制剂 HA患者的产生和/或持久性。这些研究将共同告知免疫室对于FVIII免疫反应至关重要，并建立临床前数据以翻译抗BAFF治疗去诊所。该提案中的研究和职业目标将加强Doshi博士的研究曲目使她能够过渡到专注于血液疾病的独立身体科学家，特别是血友病。