Awarded a one-year, $97,500 grant from Pachyonychia Congenita Project.
Pachyonychia congenita (PC) is characterized by excessive callus formation which is caused by thickening of the outer layer of the skin, the epidermis. To form the epidermis, the resident cells have to undergo drastic changes to lose a major fraction of their content with the help of the cellular garbage bins, the lysosomes. We could previously show that lysosomes do not work properly in PC. We therefore want to explore if modulation of lysosomes helps to ameliorate callus formation in PC.
Project Title: Lysosomes in the pathogenesis of pachyonychia congenita
Principal Investigator (PI) Name: Nicole Schwarz, PhD
PI Affiliations: Institute of Molecular and Cellular Anatomy, RWTH Aachen University
Abstract
Pachyonychia congenita (PC) is a hereditary skin disease that is caused by mutations in keratin genes 6, 16 and 17 and is characterized by painful palmoplantar keratoderma. We have previously shown that, in PC patient-derived keratinocytes, mitochondria overage and autolysosomes accumulate. In conjunction with additional functional analyses, we hypothesize that autolysosomal function is disturbed in PC which, in turn, interferes with adequate keratinocyte differentiation and consequentially leads to keratoderma. In the proposed project, we want to investigate how keratin intermediate filaments influence lysosomal function with regards to their formation, localization and acidification and if artificial acidification of lysosomes ameliorates the epidermal thickening phenotype of PC.
