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Restriction of psoriatic skin and joint disease by A20

Award Number: K08AR077065
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/05/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Restriction of psoriatic skin and joint disease by A20 - PROJECT SUMMARY: The relationship between psoriatic skin and joint disease remains enigmatic. A subset of patients with psoriasis develop arthritis, early diagnosis of which is challenging. Additionally, therapies for skin disease are less successful at treating arthritis. A20 (Tnfaip3) is a broadly-expressed protein that restricts multiple inflammatory signaling pathways and is genetically associated with both psoriasis and psoriatic arthritis in humans. However, the molecular and tissue-specific mechanisms by which A20 restricts psoriatic disease are unknown. Our preliminary data shows that A20's capacity for binding linear ubiquitin is critical for preventing distal digit psoriatic skin and joint disease in mice, with pathology requiring TNF, IL17A, and T-cells. Early disease surrounded the epidermis; therefore, we generated mice allowing inducible deletion of A20 only in keratinocytes in adulthood (A20iEKO mice). Remarkably, these mice also develop similar psoriatic skin and joint disease that requires TNF, IL17A, and T-cells. I aim to determine the immune mechanisms by which A20 dysregulation in keratinocytes orchestrates skin and joint disease. Aim 1 centers around understanding the cytokine requirements for coordinating the pathogenic immune infiltrate. In Aim 2 I will dissect the role of T- cells by determining which subsets or antigen-specific cells are critical for pathogenic cytokine secretion as well as their anatomical sites of action. Aim 3 focuses on the cell-intrinsic role of A20 in keratinocytes, where I plan to understand the mechanisms by which A20 restricts inflammatory pathways in vivo, during keratinocyte differentiation, and downstream TNFR and IL17R. Together, these studies will reveal how keratinocytes can orchestrate an inflammatory process that results in psoriatic skin and joint disease. This is relevant to NIAMS because these studies may help explain how human psoriasis is connected to psoriatic arthritis and may reveal novel therapeutic targets or biomarkers for early or potential arthritic disease. My long-term goal is to establish an independent research program studying how inflammation remains localized within epithelial tissues such as the skin. The studies described above will provide an outstanding starting point as they aim to understand how skin dysregulation can cause joint inflammation. My research background is primarily in cellular signaling and protein biochemistry. My career development aims are to build my intellectual and scientific foundation in cellular immunology and develop professional relationships with rheumatology-focused researchers. I also plan on developing key research skills in epithelial biology as well as transcriptomic and statistical analysis. These development goals will be pursued with didactic courses along with participation in seminar series, workshops, and conferences. Together with mentorship from Dr. Averil Ma, a leading molecular immunologist, and guidance from a multidisciplinary scientific advisory committee of immunologists, epithelial biologists, and genomics experts, these aims will position me for an independent research career as a physician-scientist.


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 = $189,000 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/14/2024	NON-COMPETING CONTINUATION	$189,000
														Subtotal = $189,000

Issue Date FY: 2024 ( Subtotal = $190,000 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	8/13/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/12/2023	NON-COMPETING CONTINUATION	$189,000
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	12/21/2023	SUPPLEMENT FOR EXPANSION	$1,000
														Subtotal = $190,000

Issue Date FY: 2023 ( Subtotal = $189,000 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/18/2022	NON-COMPETING CONTINUATION	$189,000
														Subtotal = $189,000

Issue Date FY: 2022 ( Subtotal = $189,000 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/8/2021	NON-COMPETING CONTINUATION	$189,000
														Subtotal = $189,000

Issue Date FY: 2021 ( Subtotal = $189,000 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/5/2021	NEW	$189,000
														Subtotal = $189,000

Grand Total All Awards = $946,000

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Restriction of psoriatic skin and joint disease by A20

Award Number: K08AR077065

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/05/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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