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Defining the antigenic determinants of the adaptive immune response in IgG4-related disease

定义 IgG4 相关疾病中适应性免疫反应的抗原决定因素

基本信息

批准号：
10284753
负责人：
Cory Perugino
金额：
$ 17.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10284753
关键词：
Affect Alleles Antigen Receptors Antigen Targeting Antigens Apoptosis Arthritis Autoantibodies Autoantigens Autoimmune Automobile Driving B cell therapy B-Cell Activation B-Lymphocytes Bioinformatics Biological Assay Biometry Blood CD4 Positive T Lymphocytes Cell Communication Cells Center for Translational Science Activities Clinical Clinical Immunology Clinical Sciences Clonal Expansion Clone Cells Collaborations Deposition Development Disease Disseminated Malignant Neoplasm Environment Epitopes Extracellular Matrix Proteins Faculty Fibrosis Fostering Foundations Funding Future Galectin 3 General Hospitals Genes Goals HLA-DR Antigens Human Hypersensitivity IgG4 Immune Immune response Immunologic Receptors Immunologics Individual Infiltration Institutes Investigation Journals Knowledge Lead Learning Lesion Libraries Light Link Mass Spectrum Analysis Massachusetts Mediating Mentors Mentorship Mesenchymal Molecular Molecular Biology Monoclonal Antibodies Organ Paper Parents Pathogenesis Pathogenicity Patients Peptide/MHC Complex Peptides Phenotype Positioning Attribute Proteins Publishing Recombinants Reporting Research Research Personnel Rheumatology Sampling Scientist Series Severity of illness Specificity Statistical Data Interpretation Systemic Scleroderma T cell receptor repertoire sequencing T cell response T-Lymphocyte T-cell receptor repertoire Tissues Training Training Activity Transforming Growth Factor beta Translational Research Tumor-infiltrating immune cells United States United States National Institutes of Health Universities Validation Work Yeasts adaptive immune response base biobank career clinical investigation clinical phenotype clinical remission cohort cytotoxic individual patient member novel patient subsets programs repository response screening single cell sequencing single-cell RNA sequencing skills tumor

项目摘要

This mentored research program aims to develop Dr. Perugino into an independent investigator studying the immunologic mechanisms of fibrosis. The research goals entail the identification of specific self-proteins driving adaptive immune responses in the context of IgG4-related disease (IgG4-RD), a recently described immune- mediated fibrotic disease. Candidate: Dr. Perugino is a junior faculty member in the Rheumatology Unit at Massachusetts General Hospital and has been conducting bench-based research since 2015. His short-term career goals are to build a stronger foundation in molecular biology, advance his skills in statistical analysis, develop proficiency in single-cell sequencing, gain expertise in creating and screening peptide-MHC yeast display libraries, and build his professional skills towards independent investigation. These goals will be supported by a series of coursework through Harvard University and the Harvard Clinical and Translational Science Center. He has recently published four first-author papers, the first identifying galectin-3 as a novel B cell self-antigen in IgG4-RD (Journal of Allergy and Clinical Immunology, 2019), the 2nd linking the diversity of auto-antibody responses with disease severity in IgG4-RD (Arthritis & Rheumatology, 2019), a 3rd establishing CD4+ T cells with cytotoxic features as likely disease drivers in systemic sclerosis (Journal of Clinical Investigation, 2020) and a 4th establishing the effector phenotype of cytotoxic CD4+ T cells in IgG4-RD (Journal of Allergy and Clinical Immunology, 2020). This work forms the foundation for this K08 proposal. Mentorship, Training Activities, and Environment: Dr. Perugino has been under the direct mentorship of Dr. Shiv Pillai since 2015 and Dr. John Stone since 2014 acting as mentors in investigation and translational research, respectively. The training plan builds upon the skills learned under this mentorship team. Guided by his advisors and collaborators, Dr. Perugino will gain proficiency in (1) single cell RNA sequencing (Dr. Alex Shalek), (2) Ig/TCR repertoire analyses (Dr. Mark Davis), (3) peptide-MHC yeast display library development (Dr. Michael Birnbaum), immune cell interactions (Dr. Michael Brenner) and biostatistical analysis (Dr. Musie Ghebremichael). Research Program: The overarching hypothesis of this proposal is that the immune response in IgG4-RD is driven by the crosstalk between B and T cells directed at specific epitopes derived from the same protein antigen. Leveraging the identification of clonal expansions of B and T cells in IgG4-RD, the proposal entails the determination of dominant B and T cell clones, which will subsequently be used to single cell clone soluble antigen receptors and use those as probes to pull down their cognate antigens. These complementary approaches, one focused on B cells (Aim 1) and the other on T cells (Aim 2), entail the validation of B and T cell responses among the largest single-center cohort of IgG4-RD bio-samples in the United States. These studies will serve as a foundation for Dr. Perugino's future goals of identifying the HLA and antigenic determinants that distinguish the clinical phenotypes of different immune-mediated fibrotic diseases, such as IgG4-RD, as an independent investigator.

这个有指导的研究项目旨在将佩鲁吉诺博士培养成一名独立的研究人员