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Pathogenic T cells in discoid lupus erythematosus

Award Number: K08AR081408
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Pathogenic T cells in discoid lupus erythematosus - PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with a predilection for affecting the head and neck that causes permanent scarring, hypopigmentation, and alopecia. DLE disproportionately affects African American women, and it severely impairs quality of life. DLE may occur alone or in the setting of systemic lupus erythematosus (SLE), and treatments for DLE are currently unsatisfactory. The DLE inflammatory infiltrate is predominantly composed of T cells, which appear to promote tissue inflammation and damage, but how they adapt to the skin environment and subsequently promote tissue injury is unknown. We recently identified an inflammatory gene program induced by the transcription factor hypoxia inducible factor (HIF) that is necessary for the survival and effector ability of pathogenic T cells in lupus-prone mice, with a similar program upregulated in human SLE. Yet, how HIF1 promotes damage and what other tissue adaptation and effector pathways are activated in skin-infiltrating T cells in DLE are not known. Based on my preliminary studies, I hypothesize that HIF1 regulates pathogenic T cell survival and effector function in DLE skin, causing inflammation and damage that may be mediated in part by enhanced cytotoxicity. This HIF1-regulated effector program also suggests a paradigm of pathogenic adaptation in tissue-infiltrating T cells with the potential to drive tissue damage. To test my hypothesis, I will determine the mechanism of HIF1 blockade in alleviating skin disease in a murine lupus model. I will also study human DLE skin and blood samples using single cell RNA sequencing to probe the developmental trajectory, phenotypic, and functional profile of T cells in human DLE. Finally, I will use imaging techniques to examine the role of cytotoxicity in tissue damage in human DLE, with parallel studies in mouse tissue. My studies will not only elucidate the role of HIF1 and cytotoxicity in DLE, but will also yield the first detailed characterization of infiltrating and circulating T cells in human DLE, paving the way for future studies to develop and evaluate novel therapeutics for this devastating disease. My proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Joseph Craft, a leader in the fields of lupus research and T cell biology. Dr. Craft's laboratory in the Yale Department of Immunobiology provides a highly collaborative and supportive research environment. To further support my training, I have assembled an advisory committee with experts in transcriptomic analyses, translational dermatology, cutaneous T cell biology, and autoimmune skin disease. My research studies and directed additional career development activities focused on computational approaches, human translational research, and biostatistics in clinical investigation will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study cutaneous autoimmune diseases including DLE.


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 = $173,340 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/2/2025	NON-COMPETING CONTINUATION	$173,340
														Subtotal = $173,340

Issue Date FY: 2024 ( Subtotal = $173,340 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/11/2024	NON-COMPETING CONTINUATION	$173,340
														Subtotal = $173,340

Issue Date FY: 2023 ( Subtotal = $173,340 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/1/2023	NEW	$173,340
														Subtotal = $173,340

Grand Total All Awards = $520,020

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Pathogenic T cells in discoid lupus erythematosus

Award Number: K08AR081408

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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