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Uncovering Architectural Features in Hyper-Adhesive Desmosomes

Award Number: F31AR088336
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/11/2026
PERIOD OF PERFORMANCE END DATE: 09/10/2028

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Uncovering Architectural Features in Hyper-Adhesive Desmosomes - Project Summary Desmosomes are junctional protein assemblies found in epithelial and cardiac tissue that assist in maintaining tissue plasticity and integrity. They are composed of transmembrane cadherins and intracellular plaque proteins plakoglobin (PG), plakophilin (PKP), and desmoplakin (DP). DP consists of a C-terminal tail domain that anchors the desmosome to intermediate filaments, central rod domain, and N-terminal head domain that binds PG and PKP. Numerous single nucleotide variants within the various domains of DP alter cell-cell adhesion, resulting in various skin disorders. Variants in the rod and tail domains have been established to impact DP dimerization and DP-intermediate filament interactions respectively. However, the disease mechanisms underlying DP head domain variants have yet to be characterized. Desmosomes have two physiologically relevant functional states, Ca2+-dependent and hyper-adhesive. Cells modulate between these states to maintain tissue plasticity and integrity in dynamic processes, such as wound healing. Previous studies have identified that Ca2+-dependent junctions can be driven to hyper-adhesion through altering DP-intermediate filament and DP-PKP interactions. However, it is unclear how desmosome and DP architecture are altered in hyper-adhesion and how the architecture impacts desmosome function. I will examine DP architecture in Ca2+ dependent and hyper-adhesive desmosomes achieved through maintaining cells in confluent culture which impacts both DP-PKP and DP- intermediate filament interactions. Immortalized keratinocytes (HaCaT) cells will be maintained in a 5-day confluent culture to promote hyper-adhesion and DP’s nanoscale architecture will be quantified using super- resolution dSTORM. My preliminary data shows that the rod domain of DP significantly increases its proximity to the plasma membrane in hyper-adhesive junctions compared to Ca2+-dependent junctions. I hypothesize this is due to the hinge region embedded in the head domain of DP undergoing a conformational change in hyper- adhesive junctions resulting in the identified change in DP rod domain localization. To expand upon these findings, the mechanism and function of the architectural change of DP in hyper-adhesive desmosomes will be examined through expression of DP constructs with domain truncations within a DP knockout HaCaT cell line. To further unravel the role of the head domain of DP, head domain variants derived from erythrokeratodermia- cardiomyopathy, skin fragility, and non-syndromic alopecia will be characterized through quantifying architecture, testing junctional integrity, and assessing tissue differentiation. This will uncover how head domain variants impact DP and desmosome architecture and function at the junctional level.


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 = $42,036 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/23/2026	NEW	$0
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/11/2026	NEW	$42,036
														Subtotal = $42,036

Grand Total All Awards = $42,036

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Uncovering Architectural Features in Hyper-Adhesive Desmosomes

Award Number: F31AR088336

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/11/2026

PERIOD OF PERFORMANCE END DATE: 09/10/2028

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