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Causative mechanisms for keloid formation

Award Number: R01AR082440
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: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Causative mechanisms for keloid formation - Project Summary/Abstract Keloids are dermal lesions that grow beyond the margin of the original wound in a tumor-like manner. Keloids can expand for several years, grow to large size and be painful, itchy and inflamed. Despite of the severe physical, psychological and social impact on patients, keloids are understudied and the treatment is unsatisfactory with high recurrence rates. Keloids also contribute to racial disparity in research and health care because prevalence is highest in populations of African ancestry. There is strong evidence for a genetically diverse basis for keloids. However, gene mutations that make patients susceptible and initiate keloids have not been identified. Identifying such causative genetic variants is fundamental for the understanding of keloid pathoetiology and for the identification of potential therapeutic targets. We previously identified several keloid candidate variants by linkage analysis and whole exome sequencing in a large cohort of 103 ethnic Yoruba families from Nigeria with heritable keloid formation. We prioritized four candidate genes variants that segregate in families, are expressed in skin and associated with other fibroproliferative disorders or are involved in wound healing. In this application we aim to determine whether the downstream effects of these four candidate gene variants induce a keloid-like phenotype in skin cells or in organotypic skin equivalents. We will investigate pathways by which the candidate variants act on skin cells. In Aim 1, we will study the roles of keloid candidate gene variants on individual skin cell types derived from human isogenic induced pluripotent stem cells (hiPSCs) carrying the respective gene mutations. We minimize background noise from biological variability by comparing isogenic mutant and wild type cells that differ only by the variant to be investigated. In Aim 2, we examine interactions between mutant fibroblasts, keratinocytes and macrophages that lead to paracrine effects guiding epithelial-mesenchymal transition and fibrosis during wound healing, using co-cultures, organotypic skin equivalents and xenotransplant mouse models. We expect that investigating the role of genes that have not been investigated in keloids will bridge knowledge gaps in keloid and wound healing research and will identify novel factors that put individuals at risk for keloid development.


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: 2025 ( Subtotal = $421,796 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/16/2025	NON-COMPETING CONTINUATION	$30,439
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	10/28/2024	NON-COMPETING CONTINUATION	$391,357
														Subtotal = $421,796

Issue Date FY: 2024 ( Subtotal = $447,738 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/20/2023	NEW	$447,738
														Subtotal = $447,738

Grand Total All Awards = $869,534

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Causative mechanisms for keloid formation

Award Number: R01AR082440

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: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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