Project 461300

ITCH: Itch is a debilitating symptom experienced by 40% of the elderly. Itch can have severe impact on quality of life, cause extreme stress and depression, and is the most common skin complaint in the elderly. Currently, many of the current therapeutic interventions for itch are not suitable for the elderly due to their adverse effects, pointing to an urgent medical need. GRANZYME B: Granzyme B is a protein that plays a key role in the body's normal immune response and is present at low levels in healthy individuals. However, our team has shown that high levels of active Granzyme B are found in the skin of the elderly and in patients with itchy, inflammatory skin diseases. Further, it has been demonstrated that Granzyme B levels in the blood are linked to multiple measures of itch severity. In an experimental model of aging skin, we have early evidence that suggests that inhibiting Granzyme B will prevent itch and inflammatory skin. Our team has also recently developed a new topical medication that can inhibit Granzyme B activity and reduce disease severity in experimental models of itchy skin diseases. PROPOSED PROJECT AND IMPACT: We will comprehensively investigate the relationship between Granzyme B levels and measures of itch using aging human skin specimens (collected with full informed consent). We will also use a newly-developed technology to discover unknown functions of Granzyme B in aging itchy skin. Finally, we will use experimental models of aging itchy skin to test the efficacy of our new topical medication in alleviating itch. Taken together, our findings will advance the development of our Granzyme B-targeting medication towards clinical approval and improving patient outcomes.