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Molecular mechanisms controlling skin heterogeneity

Award Number: R01AR081322
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: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027
AWARD TERMINATION DATE: 10/19/2026

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Molecular mechanisms controlling skin heterogeneity - Different regions of the skin vary in their characteristics such as thickness, pigmentation, innervation, and presence, size and density of hair follicles and sweat glands, that are reflected in differential responses to injury and disease. As examples, androgenetic alopecia is limited to the scalp; acne predominates in facial skin; psoriasis is often most prominent in extensor regions; palmoplantar keratoderma is limited to palms and soles; and vitiligo can appear in symmetrical patterns. While regional characteristics of the skin are established during fetal development, positional information must be retained in the skin throughout life to allow for maintenance of regional characteristics and their re-establishment in wound healing. Positional information is known to reside in the skin dermis, but its molecular basis is poorly understood. To address this question, we propose the following Specific Aims. AIM 1: To identify candidate factors and areas of chromatin involved in establishing skin heterogeneity in embryogenesis we will analyze transcriptional profiles through single cell RNA-seq, and chromatin structure via single cell ATAC-seq, in distinct regions of developing skin to identify those that show region-specific expression or openness, respectively. AIM 2: (i) To determine which of these candidate factors and chromatin areas may also be responsible for maintaining regional skin heterogeneity in adult life, we will perform the same analyses on the corresponding areas of adult skin. (ii) We hypothesize that epigenetic mechanisms contribute to maintenance of regional skin characteristics. To test this, we will first identify patterns of DNA methylation and histone modifications that characterize developing dermis in specific skin regions by carrying out Bisulfite-seq to reveal sites of DNA methylation, and CUT&RUN for histone modifications that mark enhancers and active, repressed, or poised genes. We will then ask which of these patterns are maintained in adult dermal cells from the same regions. AIM 3: To test the functions of candidate regulators in directing and maintaining region-specific differentiation programs, we will use inducible genetic tools to delete the corresponding genes in developing or adult mouse dermis in vivo. Together, these experiments provide a comprehensive and unbiased approach to identify novel mechanisms that establish and maintain skin heterogeneity. Improved understanding of these mechanisms has potential to reveal new therapeutic targets in wound healing and in common and rare diseases that affect specific skin regions and have a major negative impact on quality of life; data obtained in this project will also inform strategies for generating specific skin types, including hair follicle- and sweat gland-bearing skin, for reparative skin grafting.


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: 2027 ( Subtotal = $0 )
2027	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	10/19/2026	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $593,836 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/22/2026	NON-COMPETING CONTINUATION	$593,836
														Subtotal = $593,836

Issue Date FY: 2025 ( Subtotal = $626,589 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/17/2025	NON-COMPETING CONTINUATION	$524,371
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	8/27/2025	SUPPLEMENT FOR EXPANSION	$102,218
														Subtotal = $626,589

Issue Date FY: 2024 ( Subtotal = $627,664 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/18/2024	SUPPLEMENT FOR EXPANSION	$102,218
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/24/2024	NON-COMPETING CONTINUATION	$525,446
														Subtotal = $627,664

Issue Date FY: 2023 ( Subtotal = $563,698 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/17/2023	NON-COMPETING CONTINUATION	$563,698
														Subtotal = $563,698

Issue Date FY: 2022 ( Subtotal = $571,134 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/20/2022	NEW	$571,134
														Subtotal = $571,134

Grand Total All Awards = $2,982,921

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Molecular mechanisms controlling skin heterogeneity

Award Number: R01AR081322

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: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

AWARD TERMINATION DATE: 10/19/2026

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