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Modeling KRT5-linked skin disease to define key pathogenic drivers and novel therapeutic strategies

Award Number: R21AR087042
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: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Modeling KRT5-linked skin disease to define key pathogenic drivers and novel therapeutic strategies - Summary/Abstract: Keratinocytes must strongly adhere together within the multi-layered epidermis to resist mechanical stress and form a protective shield for the body. They accomplish this by linking robust keratin (KRT) intermediate filaments to cell-cell junctions called desmosomes, assembling a multi-cellular scaffold to bolster the epidermis. Underscoring the mechanical function of KRTs, mutations in KRT5 cause skin fragility disorders including epidermolysis bullosa simplex (EBS), characterized by lifelong painful skin erosions. Despite knowing its genetic etiology for over 30 years, EBS has no FDA-approved therapy; current treatments merely focus on wound care, protective dressings, pain control, along with secondary infections, dehydration, and malnutrition. Existing pre-clinical EBS models have not led to therapeutic advances; these include Krt5 knockout (KO) mice that rapidly succumb to skin blistering, limiting their suitability for investigating EBS pathogenesis. This project utilizes an organotypic skin model in which CRISPR/Cas9-edited TERT-immortalized human epidermal keratinocytes (THEKs) generate mature epidermis within two weeks. Importantly, this model is compatible with on-site live confocal microscopy platforms, allowing simultaneous imaging of cytoskeletal/junctional components and biosensors to delineate key pathogenic drivers (and druggable targets) in real-time in a 3D disease model. In preliminary work, KRT5-deficient THEKs demonstrated weakened cell-cell junctions and rupture of basal layer keratinocytes, replicating EBS pathology. Intriguingly, a subset of KO lines were able to mitigate KRT5 loss and restore epidermal integrity. RNA sequencing of control, KO, and compensated (KO-comp) cells was used to identify candidate drivers of KRT5-linked pathology and this phenotypic rescue; this revealed two putative compensatory mechanisms: (1) alternate KRT isoform expression; and (2) type 1 interferon (IFN) modulation. Aim 1 tests the hypothesis that up-regulation of alternate KRTs can mitigate KRT5 loss. Ectopic gene delivery and pharmacologic approaches will be used to induce wound- (KRT6/16) or differentiation-associated KRTs (KRT1/10). To define how keratinocytes induce compensatory KRTs, the experiments will deploy biosensors for mechano-sensitive MAP kinases previously linked to KRT expression and EBS. Aim 2 tests the hypothesis that aberrant type 1 IFN signaling due to KRT5 deficiency exacerbates keratinocyte fragility. Use of IFN biosensors in control, KO, and KO-comp cells will delineate how this pathway triggers basal keratinocyte shearing vs. upward migration/differentiation in epidermis. In both aims, drugs already FDA-approved to modulate MAP kinase and IFN signaling in other diseases will be tested for potential to rescue keratinocyte adhesion and tissue integrity. In sum, this project leverages new EBS models to understand its pathogenesis and identify rational treatment approaches. While this R21 tests two likely pathogenic pathways, the studies will validate a platform that could be used for screening FDA-approved drug libraries for repurposing. Moreover, though the initial focus is EBS, this model could be readily adapted to identify needed therapeutic strategies for other orphan genetic 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: 2026 ( Subtotal = $401,807 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/10/2026	NEW	$401,807
														Subtotal = $401,807

Grand Total All Awards = $401,807

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Modeling KRT5-linked skin disease to define key pathogenic drivers and novel therapeutic strategies

Award Number: R21AR087042

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: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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