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

Award Number: K08AR079615
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $174,960 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/18/2025	NON-COMPETING CONTINUATION	$174,960
														Subtotal = $174,960

Issue Date FY: 2024 ( Subtotal = $174,960 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	9/4/2024	NON-COMPETING CONTINUATION	$174,960
														Subtotal = $174,960

Issue Date FY: 2023 ( Subtotal = $174,960 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/23/2023	NON-COMPETING CONTINUATION	$174,960
														Subtotal = $174,960

Issue Date FY: 2022 ( Subtotal = $174,960 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/23/2022	NON-COMPETING CONTINUATION	$174,960
														Subtotal = $174,960

Issue Date FY: 2021 ( Subtotal = $174,960 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/9/2021	NEW	$174,960
														Subtotal = $174,960

Grand Total All Awards = $874,800

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

Award Number: K08AR079615

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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