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The mutational mechanisms shaping melanocytes in human skin

Award Number: R01AR080626
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/17/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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The mutational mechanisms shaping melanocytes in human skin - Project Summary/Abstract As a barrier organ, skin forms the main defense against ultraviolet (UV) radiation, a potent mutagen emitted by the sun. The mutational damage incurred through this role can lead to melanoma, the deadliest form of skin cancer. Contrary to expectations, melanoma is more common on body sites that are only exposed to UV radiation intermittently, such as the back and shoulder, rather than body sites exposed more continuously, such as the head/neck areas. We recently reported the first catalogue of somatic mutations in melanocytes from normal human skin and discovered that melanocytes from the back/trunk had higher mutation burdens than donor-matched melanocytes from the head/neck areas. Based on our mutational observations and the anatomic patterns of melanoma, we hypothesize that melanocytes on the head/neck areas have evolved mechanisms to accumulate mutations more slowly than melanocytes from other body sites – likely an adaptation to counterbalance the higher levels of cumulative sun exposure affecting those sites. If true, this would alter prevention strategies. Moreover, a better understanding of the mechanisms by which melanocytes accumulate mutations would reveal molecular strategies to slow down this process and reduce the incidence of melanoma. We will test our hypothesis in aim 1 by comparing somatic mutations in melanocytes of different anatomic origins within-people and in aim 2 by cataloguing somatic mutations in site-matched melanocytes across people who offer detailed histories of sun exposure. These studies will offer correlative data implicating the main factors driving up the mutation burdens in melanocytes. A major obstacle to these studies is that it is difficult to measure somatic mutations in individual cells at a high degree of accuracy. However, we recently pioneered a workflow to call mutations in individual melanocytes at nearly 100% specificity and sensitivity. To complement these observational studies, in aim 3, we will measure in vitro the rates at which melanocytes of different anatomic origins repair DNA damage and dissect the main mechanisms regulating this process. Towards this goal, we have developed assays to measure UV-radiation-induced DNA damage at single base- pair resolution in tissue-cultured cells. Taken together, the scientific approaches employed in this proposal are technologically innovative and will illuminate the mutational mechanisms operating on melanocytes in normal human skin, addressing major gaps in knowledge that have vexed the skin research community.


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: 2026 ( Subtotal = $363,958 )
2026	2026	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	4	12/16/2025	NON-COMPETING CONTINUATION	$363,958
														Subtotal = $363,958

Issue Date FY: 2025 ( Subtotal = $393,718 )
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	3	11/14/2024	NON-COMPETING CONTINUATION	$365,305
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	001	3	6/3/2025	NON-COMPETING CONTINUATION	$28,413
														Subtotal = $393,718

Issue Date FY: 2024 ( Subtotal = $399,002 )
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	2	11/20/2023	NON-COMPETING CONTINUATION	$370,208
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	001	2	6/14/2024	NON-COMPETING CONTINUATION	$28,794
														Subtotal = $399,002

Issue Date FY: 2023 ( Subtotal = $426,693 )
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	1	2/16/2023	NEW	$426,693
														Subtotal = $426,693

Grand Total All Awards = $1,583,371

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The mutational mechanisms shaping melanocytes in human skin

Award Number: R01AR080626

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/17/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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