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Non-canonical transcriptional activation of MITF in pigment cells.

Award Number: K99AR084551
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Non-canonical transcriptional activation of MITF in pigment cells. - Project Summary MITF, particularly the melanocyte-restricted m-MITF isoform, is a key transcription factor that regulates melanocyte differentiation, survival, and pigmentation. Its expression is dynamically regulated by the MC1R receptor through the PKA signaling pathway. For decades, it was thought that CREB1 was the PKA-controlled transcription factor that drove m-MITF transcription. However, I have discovered that a non-canonical mechanism activates m-MITF independent of CREB1 and its redundant paralogs. This mechanism requires the transcriptional co-activator CRTC, which must be recruited to m-MITF promoter DNA through an unknown factor. We propose here to define this non-canonical mechanism, discover its unknown regulators, and characterize the precise molecular interactions required for m-MITF transcriptional activation. Specifically, we will 1) generate a toolkit of mutant cell lines designed to perturb select events in PKA signaling and dissect the differences between non-canonical and canonical regulation, 2) perform functional genomic screens to unveil new regulators of m- MITF using cellular proliferation and transcriptional reporter readouts, and 3) investigate physical interactions between identified regulators and the m-MITF promoter to develop a molecular model for the non-canonical mechanism. As a feature of each of these aims, we will apply our findings to genetically modified, iPSC-derived primary melanocytes and organotypic skin reconstitutions to address this mechanism's role in physiological tissue pigmentation. This work will deepen our understanding of the molecular biology of pigmentation and give insight into PKA signaling in other specialized cell types. It will lay the foundation for molecular approaches to manipulate m-MITF in a melanocyte-specific manner for the chemoprevention and treatment of numerous sun- and pigmentation-related conditions, including skin cancer and aging.


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 = $107,784 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/8/2026	NEW	$107,784
														Subtotal = $107,784

Grand Total All Awards = $107,784

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Non-canonical transcriptional activation of MITF in pigment cells.

Award Number: K99AR084551

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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