Document text
Principal Investigator: ANDREW P. KOWALCZYK
Organization: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
Fiscal Year: 2024
Award: $442,244
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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), and severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome caused by
DSG1 loss of function mutations. Our previous studies of PV revealed that desmosomal proteins are
associated with lipid rafts, and our recent findings indicate that a mutation in the Dsg1TMD that
abrogates lipid raft association, compromises desmosome formation, and causes SAM syndrome.
Lipid rafts are important for a variety of cellular functions, including signaling, endocytosis and
membrane domain formation. The important role of lipid rafts in regulating Dsg function in different
skin diseases underscores the importance of Dsg association with lipid rafts in normal desmosome
function and epidermal homeostasis. We hypothesize that Dsg association with rafts is required for
desmosome assembly, segregation from adherens junctions, and for Dsg adhesive and signaling
activities necessary for epidermal homeostasis. The experiments outlined in this proposal are
designed to reveal the raft targeting features of desmosomal cadherins, how raft association
regulates desmosome and adherens junction membrane domain formation, and how loss of Dsg raft
association leads to SAM syndrome. 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 function.
Terms: <7S Gamma Globulin><Adherens Junction><Adhering Junction><Adhesions><Adhesive Junction><Adhesives><Allergy><Anchoring Junction><Autoantibodies><Autoimmune><Autoregulation><Binding><Biological><Biophysics><Bleb><Blister><Bulla><Bullous Lesion><Cadherins><Calcium Ion Signaling><Calcium Signaling><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Function><Cell Interaction><Cell Junctions><Cell Line><Cell Membrane Lipid Rafts><Cell Membrane Lipids><Cell Physiology><Cell Process><Cell Signaling><Cell membrane><Cell surface><Cell-Cell Adhesion><Cell-to-Cell Interaction><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Complex><Cutaneous Disorder><Cytoplasmic Membrane><Data><Dermatitis><Dermatoses><Desmosomes><Disease><Disorder><Dysfunction><Endocytosis><Endoplasmic Reticulum><Epithelium><Ergastoplasm><Exposure to><Foundations><Functional disorder><Gametes><Genetic Alteration><Genetic Change><Genetic Models><Genetic defect><Germ Cells><Germ-Line Cells><Hereditary><Homeostasis><Hypersensitivity><IgG><Immunoglobulin G><Inherited><Intercellular Junctions><Intermediate Filaments><Intracellular Communication and Signaling><Lipids><Macula Adherens><Mechanics><Mediating><Membrane><Membrane Lipids><Membrane Microdomains><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic><Modeling><Molecular Dynamics Simulation><Molecular Interaction><Morphology><Mutation><Nature><Node of Bizzozero><Null Cells><Null Lymphocytes><Outcome><Outcome Study><Pemphigus><Pemphigus Vulgaris><Physiological Homeostasis><Physiopathology><Plasma Membrane><Play><Property><Proteins><Regulation><Reproductive Cells><Role><SAM syndrome><Severe dermatitis, Allergies and Metabolic wasting syndrome><Sex Cell><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Diseases><Skin Diseases and Manifestations><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Spot Desmosome><Sterols><Strains Cell Lines><Structure><Subcellular Process><Surface Proteins><Syndrome><TM Domain><Testing><Transmembrane Domain><Transmembrane Region><Vesication><Wound Repair><autoimmune antibody><autoreactive antibody><biologic><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><cell biology><cultured cell line><cutaneous disease><dermal disease><dermal disorder><design><designing><desmoglein 3><desmoglein III><desmosomal glycoprotein 3><develop therapy><experiment><experimental research><experimental study><experiments><genome mutation><human disease><initial cell><insight><intervention development><keratinocyte><lipid raft><loss of function mutation><mechanic><mechanical><membrane structure><migration><molecular dynamics><mouse genetics><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><optic imaging><optical imaging><pathophysiology><plasmalemma><resilience><resilient><segregation><self reactive antibody><severe dermatitis, multiple allergies and metabolic wasting syndrome><sexual cell><skin disorder><social role><therapeutic agent development><therapeutic development><therapy development><treatment development><wasting><wound healing><wound recovery><wound resolution>