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MITF from control of pigmentation to melanoma risk

Award Number: R01AR043369
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: 02/20/1996
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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MITF from control of pigmentation to melanoma risk - Abstract Human skin phototypes are routinely described in a gradient of 1 (redhaired) to 6 (dark constitutive pigment) which correlates with UV sensitivity and risk of melanoma. Parallel to this gradient is the increase of nevi (moles) from darker to lighter phototypes, a gradient which abruptly drops at phototype 1 (redhaired) where visible nevi are unexpectedly rare. We hypothesized, and verified in murine models, that BRAFV600E- induced nevi in redhaired mice are “invisible” but actually significantly more abundant compared to genetically matched black mice. They are clinically inapparent due to lack of dark eumelanin, but are easily identified via fluorescence tagging, and associated with profoundly elevated spontaneous melanoma transformation and UVA-induced melanoma risk in redhaired mice. This melanoma risk was traced to red pigment because “albino-redhaired” mice lack all pigment and are protected from either spontaneous (previously published), UVA-induced, or peroxide-induced melanoma. Spontaneous and UVA-induced “invisible” nevi and melanoma-genesis are proposed for study in Aims 1 and 2 for NRASQ61R pigment models, the 2nd most common human nevus and melanoma oncogene, to complement our extensive unpublished data for BRAFV600E. Several small molecule approaches will be tested to potentially mitigate pheomelanin-induced melanoma risk including induction of dark eumelanin synthesis. One such example was already seen to ”reveal” visible lesions in the “invisible” nevus- bearing redhaired mice. In addition, the fluorescent nevi, engineered into isogenic pigment backgrounds, will be flow-sorted from skin and transcriptomically scrutinized to mechanistically dissect the pathways and genes (including redox) that mediate the elevated melanoma risk among fair skinned individuals. Only a minority of melanomas arise from pre-existing nevi, so we use our models to examine both nevi and overall melanoma risk. We also discovered that the Parkinson’s Disease therapy L-Dopa significantly elevates pheomelanin synthesis in redheads. Separate from being a dopamine precursor, L-Dopa is coincidentally a chemical intermediate in melanin biosynthesis. Parkinson’s Disease and melanoma have long been associated with one another, but lacking a mechanistic explanation. We observed that low dose L-Dopa significantly elevates melanoma risk in BRAFV600E redhaired, but not in albino-red mouse models (which cannot make pheomelanin or eumelanin). Aim 3 will test L-Dopa’s melanoma causality in NRASQ61R redhaired models and whether topical skin darkening may modify the enhanced melanoma risk already observed for BRAFV600E. Finally, Aim 4 will examine the hypothesis that MITF regulates expression of an anti-oxidant pathway which includes enzymes controlling regeneration of reduced NADPH and glutathione—key factors buffering melanocyte oxidative stress. One such enzyme, the mitochondrial enzyme NNT, was recently shown to modulate melanocyte redox and melanosome differentiation. We will test evidence that NNT is a transcriptional target of MITF and functionally scrutinize a newly identified sequence variant in NNT, nominated by NCI collaborators as a candidate familial melanoma gene in humans.


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 = $484,419 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	30	3/30/2026	NON-COMPETING CONTINUATION	$484,419
														Subtotal = $484,419

Issue Date FY: 2025 ( Subtotal = $484,419 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	29	4/22/2025	NON-COMPETING CONTINUATION	$484,419
														Subtotal = $484,419

Issue Date FY: 2024 ( Subtotal = $519,228 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	28	5/22/2024	NON-COMPETING CONTINUATION	$37,470
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	28	2/7/2024	NON-COMPETING CONTINUATION	$481,758
2024	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	27	2/6/2024	COMPETING CONTINUATION	$0
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	26	2/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $519,228

Issue Date FY: 2023 ( Subtotal = $642,287 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	27	6/16/2023	COMPETING CONTINUATION	$0
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	27	2/3/2023	COMPETING CONTINUATION	$552,287
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	27	8/9/2023	SUPPLEMENT FOR EXPANSION	$90,000
														Subtotal = $642,287

Issue Date FY: 2022 ( Subtotal = $358,498 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	26	5/30/2022	NON-COMPETING CONTINUATION	$32,591
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	26	2/18/2022	NON-COMPETING CONTINUATION	$325,907
														Subtotal = $358,498

Issue Date FY: 2021 ( Subtotal = $351,255 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	4/15/2021	NON-COMPETING CONTINUATION	$351,255
														Subtotal = $351,255

Issue Date FY: 2020 ( Subtotal = $362,119 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	24	4/6/2020	NON-COMPETING CONTINUATION	$362,119
														Subtotal = $362,119

Issue Date FY: 2019 ( Subtotal = $362,119 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	2/22/2019	NON-COMPETING CONTINUATION	$362,119
														Subtotal = $362,119

Issue Date FY: 2018 ( Subtotal = $362,119 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	22	6/6/2018	COMPETING CONTINUATION	$27,341
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	22	3/8/2018	COMPETING CONTINUATION	-$5,187
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	22	3/7/2018	COMPETING CONTINUATION	$367,306
2018	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	21	6/6/2018	NON-COMPETING CONTINUATION	-$27,341
														Subtotal = $362,119

Issue Date FY: 2017 ( Subtotal = $342,200 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	21	8/24/2017	NON-COMPETING CONTINUATION	$34,220
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	21	3/1/2017	NON-COMPETING CONTINUATION	$307,980
														Subtotal = $342,200

Issue Date FY: 2016 ( Subtotal = $342,200 )
2016	2016	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	3/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$342,200
														Subtotal = $342,200

Issue Date FY: 2015 ( Subtotal = $342,200 )
2015	2015	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	2/25/2015	NON-COMPETING CONTINUATION	$342,200
														Subtotal = $342,200

Issue Date FY: 2014 ( Subtotal = $342,200 )
2014	2014	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	3/21/2014	NON-COMPETING CONTINUATION	$342,200
														Subtotal = $342,200

Issue Date FY: 2013 ( Subtotal = $342,200 )
2013	2013	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	17	2/20/2013	COMPETING CONTINUATION	$342,200
2013	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	2/20/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $342,200

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	3/20/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $404,198 )
2011	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	6/21/2011	NON-COMPETING CONTINUATION	$404,198
														Subtotal = $404,198

Issue Date FY: 2010 ( Subtotal = $394,231 )
2010	2010	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	15	7/1/2010	SUPPLEMENT FOR EXPANSION	$33,365
2010	2010	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	5/26/2010	NON-COMPETING CONTINUATION	$360,866
														Subtotal = $394,231

Issue Date FY: 2009 ( Subtotal = $363,949 )
2009	2009	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	14	6/18/2009	NON-COMPETING CONTINUATION	$363,949
2009	2008	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	13	5/21/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$198,022
2009	2008	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	5/21/2009	NON-COMPETING CONTINUATION	-$198,022
														Subtotal = $363,949

Grand Total All Awards = $9,778,940

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MITF from control of pigmentation to melanoma risk

Award Number: R01AR043369

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: 02/20/1996

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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