The repair of injuries is dominated by a tendency to re-establish tissue continuity rather than restoring the structure of the original tissue. This process results in scarring and fibrosis, which is a major medical problem spanning diseases in all organ systems. This application focuses on a compound that has been shown to be highly effective in reducing scarring as systemic therapy in mice. The compound is an injury- targeted form of the well-established anti-scarring protein, decorin. The proposal is to optimize the targeted decorin for subsequent pre-clinical studies and clinical trials. Structure function studies on the wound- homing peptide that delivers decorin to the sites of injury will be conducted to optimize the structure of the peptide and the fusion protein for injury-homing applications. Preliminary results suggest that a truncated form of the peptide may be even more effective than the original 9-amino acid peptide in delivering payload to injuries. This and other variants of the peptide will be tested to a compound most effective in delivering decorin to wounds. Decorin produced in mammalian cells heterogeneous because of variation in the presence and structure of the single glycosaminoglycan chain attached to the decorin core protein. This heterogeneity could cause problems in terms of regulatory approvals. There is evidence to the effect that the glycosaminoglycan chain may not be needed for the anti-scarring activity, motivating in vivo testing of homogeneous, glycosaminoglycan-free targeted decorin as an anti-scarring agent. The anti-scarring activity of system in which the wound-homing peptide and decorin are co-administered rather than covalently attached to one another, will also be explored. If active, the co-administration system would be simpler and could also be easily adapted to the targeting of other injury-targeted drugs. The ensuing results will allow the selection of the most promising targeted decorin compound for further preclinical studies. These studies may result in a new systemic treatment that can limit the permanent damage caused by fibrosis in injured and inflamed tissues.
Public Health Relevance: Scarring (fibrosis) resulting from injury, inflammation and vascular problems is a major medical problem spanning diseases such as heart attack, stroke, liver cirrhosis and wounds because scarring prevents restoration of the original tissue. A natural inhibitor of scarring, decorin, inhibits scar formation in animal models. We have improved the activity of decorin by adding a homing signal that directs decorin to sites of injury, and propose here studies that will advance the targeted decorin toward the clinic.
Thesaurus Terms: Amino Acids;Animal Model;Animal Models And Related Studies;Animals;Apoplexy;Body Tissues;Brain Vascular Accident;Cardiac Infarction;Cell Communication And Signaling;Cell Signaling;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Chimera Protein;Chimeric Proteins;Chondroitin Sulfate Proteoglycan;Cicatrix;Clinic;Clinical Trials;Core Protein;Data;Disease;Disorder;Drug Delivery;Drug Delivery Systems;Drug Targeting;Fibrosis;Fusion Protein;Glycosaminoglycans;Grant;Hepatic Cirrhosis;Heterogeneity;Homing;In Vitro;Injury;Intracellular Communication And Signaling;Loinc Axis 4 System;Liver Cirrhosis;Mammalian Cell;Medical;Mice;Mice Mammals;Modeling;Mucopolysaccharides;Murine;Mus;Mutate;Myocardial Infarct;Myocardial Infarction;Organ System;Peptides;Phase;Process;Proteins;Proteoglycan;Recombinants;Sys-Tx;Scars;Signal Transduction;Signal Transduction Systems;Signaling;Site;Skin;Structure;System;Systemic Therapy;Testing;Tissues;Toxic Effect;Toxicities;Variant;Variation;Work;Aminoacid;Base;Biological Signal Transduction;Body System;Brain Attack;Cardiac Infarct;Cerebral Vascular Accident;Cerebrovascular Accident;Clinical Investigation;Coronary Attack;Coronary Infarct;Coronary Infarction;Decorin;Disease/Disorder;Gene Product;Heart Attack;Heart Infarct;Heart Infarction;Immunogenicity;Improved;In Vivo;Inhibitor;Inhibitor/Antagonist;Injured;Injury And Repair;Model Organism;Peptide Structure;Pre-Clinical;Pre-Clinical Study;Pre-Clinical Trial;Preclinical;Preclinical Study;Preclinical Trial;Prevent;Preventing;Restoration;Stroke;Tumor;Vascular Inflammation;Wound
