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Regulators of Melanocyte Stem Cell Migration and Melanoma Initiation in Response to Cutaneous UVB Irradiation

Award Number: R01AR075755
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Regulators of Melanocyte Stem Cell Migration and Melanoma Initiation in Response to Cutaneous UVB Irradiation - PROJECT SUMMARY / ABSTRACT Melanocyte stem cells (McSCs) of the hair follicle can serve as a reservoir for melanocyte replenishment to the epidermal layer of the skin. This property has been demonstrated in patients with the depigmentation disease vitiligo, in which new pigmentation is found in a peri-follicular pattern surrounding hair follicles, following treatment with narrow-band ultraviolet B radiation (UVB). Unfortunately, repigmentation through UVB therapy is neither widespread nor durable. On the other hand, McSCs harboring mutations can serve as cells of origin for melanoma, the deadliest of skin cancers. Melanoma in this context can be initiated by the activation of McSCs in response to UVB exposure. It is our long-term goal to identify the molecular mechanisms through which UVB alters the activation and migration of McSCs to ultimately provide a significant impact leading to the improvement of vitiligo treatment and new methods of melanoma prevention. Our preliminary data indicate that a pro-inflammatory state in the skin, induced by UVB exposure, facilitates McSC translocation to the epidermis and melanoma initiation from mutant McSCs. We have also shown that loss of function in the architectural chromatin remodeling factor Hmga2 results in impairment of both McSC translocation and melanoma initiation through a cell extrinsic mechanism. The underlying molecular events through which inflammation and Hmga2 regulate these processes have not been identified. TNF signaling and neutrophil/macrophage recruitment have been determined as potential mediators of McSC proliferation and migration, and melanoma initiation from McSCs. It is the central hypothesis of this proposal that UVB-mediated McSC translocation, and melanoma initiation from McSCs, requires inflammatory cell influx and TNF signaling, which is induced by tissue-specific Hmga2 transcriptional regulation. In this proposal, we will test whether specific cell populations and signaling pathways are responsible for UVB-mediated McSC translocation and melanoma initiation via Aim 1) directed at the necessity of inflammation mediated recruitment of neutrophils and macrophages, Aim 2) directed at the necessity and sufficiency of cytokine signaling mediated by Tnf-alpha, and Aim 3) directed at defining the cell population and downstream transcription changes dependent upon Hmga2. Our approach will utilize our innovative model system to define these processes in vivo, using deletion/overexpression by cell specific genetic manipulation, antibody and small molecule neutralization of cell populations and signaling pathways, and transcriptomic profiling on isolated cell populations. Understanding and conclusively defining the cell populations and transcriptomic changes occurring during UVB-mediated McSC translocation and melanoma initiation will lead to testing of novel strategies for vitiligo treatment and melanoma prevention. These goals are directly in line with the mission at NIAMS to improve the health of patients suffering from skin diseases.


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: 2024 ( Subtotal = $320,034 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/7/2024	NON-COMPETING CONTINUATION	$296,939
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/7/2024	NON-COMPETING CONTINUATION	$23,095
														Subtotal = $320,034

Issue Date FY: 2023 ( Subtotal = $330,390 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/18/2023	NON-COMPETING CONTINUATION	$330,390
														Subtotal = $330,390

Issue Date FY: 2022 ( Subtotal = $327,498 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/9/2022	NON-COMPETING CONTINUATION	$29,773
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/28/2022	NON-COMPETING CONTINUATION	$297,725
														Subtotal = $327,498

Issue Date FY: 2021 ( Subtotal = $156,480 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	2	6/9/2021	NON-COMPETING CONTINUATION	$0
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	4/16/2021	NON-COMPETING CONTINUATION	$156,585
2021	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/24/2021	NEW	-$164,936
2021	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	4/12/2021	NEW	$164,831
														Subtotal = $156,480

Issue Date FY: 2020 ( Subtotal = $496,778 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/10/2020	NEW	$139,426
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/9/2020	NEW	$164,936
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	1	9/25/2020	NEW	$192,416
														Subtotal = $496,778

Grand Total All Awards = $1,631,180

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Regulators of Melanocyte Stem Cell Migration and Melanoma Initiation in Response to Cutaneous UVB Irradiation

Award Number: R01AR075755

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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