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Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris

Award Number: R01AR081883
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris - Project Summary/Abstract Desmosomes are adhesive intercellular junctions that play critical roles in epidermal homeostasis by mediating robust cell-cell adhesion and by modulating signaling pathways that regulate epidermal differentiation. The importance of desmosomes is highlighted by numerous autoimmune and inherited skin diseases that compromise desmosome function and cause epidermal fragility. These diseases include pemphigus vulgaris (PV), a severe autoimmune epidermal blistering disease caused by autoantibodies (IgG) directed against the desmosomal cadherin desmoglein-3 (Dsg3). The precise mechanism by which PV IgG disrupt desmosome adhesion and trigger signaling pathways associated with the loss of adhesion are not well understood. This limitation has hindered the development of new therapies that can spare or eliminate the need for immunosuppressive treatments which can pose risks for patient safety. In the current proposal, we outline a series of cutting edge imaging approaches that will resolve with previously unachievable detail precisely how PV IgG disrupt adhesion. Aim 1 studies will determine how pemphigus IgG disrupt desmosome dynamics, architecture, and function using cryo-EM, live cell imaging, and molecular dynamics simulations. In Aim 2, we focus on how keratinocytes respond to pemphigus IgG and the role of Ca2+ signaling and endoplasmic reticulum stress pathways in the endocytosis of desmosomal proteins and in the inflammatory responses associated with desmosome disruption in both cultured cells and patient tissues. The outcome of these studies will produce fundamentally new conceptual models for desmosome regulation and will form a foundation for the treatment of skin diseases associated with loss of desmosome adhesion.


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: 2024 ( Subtotal = $569,126 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	8/15/2024	NON-COMPETING CONTINUATION	$569,126
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/20/2023	NEW	$0
														Subtotal = $569,126

Issue Date FY: 2023 ( Subtotal = $604,539 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/30/2023	NEW	$4,632
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/29/2023	NEW	$599,907
														Subtotal = $604,539

Grand Total All Awards = $1,173,665

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Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris

Award Number: R01AR081883

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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