Project Summary/Abstract Research: Epidermal homeostasis relies on two balanced processes: (1) mitotic keratinocytes in the basal layer must maintain healthy organelles despite damage due to aging and ultraviolet radiation in order to continually regenerate the upper layers and (2) post-mitotic cells in the outer layers must degrade organelles to form a compact, protective barrier for the body. The mechanisms governing these fundamental processes are poorly understood and this hampers our ability to restore epidermal barrier function in diseases like ichthyosis and atopic dermatitis and to prevent skin carcinogenesis and aging. My research will test the hypothesis that the epidermis relies upon autophagy pathways to drive organelle degradation as a constitutive process during cornification and in an inducible manner to repair damaged organelles. The proposed experiments apply super-resolution microscopy to image single organelle dynamics and degradation in live epidermis. The results will improve our understanding of the role of autophagy in epidermal homeostasis and differentiation and could suggest novel clinical uses of autophagy modulators for treatment of skin disease. Candidate: Cory Simpson earned his M.D. and Ph.D. from Northwestern Univ. in 2012, completed clinical dermatology training at the Univ. of Pennsylvania in 2016, and sees patients with blistering disease, barrier disorders, and skin cancer. Dr. Simpson is pursuing post-doctoral training in the lab of Dr. Erika Holzbaur, Ph.D., where he is coupling live organotypic human and murine skin with innovative microscopy approaches. The career development plan will allow Dr. Simpson to build on his training in keratinocyte biology to establish an independent research program defining mechanisms of organelle degradation during epidermal differentiation and upon environmental damage. Support from a K08 award will position Dr. Simpson to attain his goal of becoming an R01-funded investigator directing an academic lab focused on modulating keratinocyte organelle turnover to augment skin barrier function and prevent aging- and UV radiation-induced skin damage. Environment: The mentor, Dr. Holzbaur, is an NIH-funded Penn professor who provides (1) renowned expertise in organelle trafficking and autophagy in disease models, (2) unrivaled live cell imaging experience and state-of-the-art microscopes, and (3) exceptional mentorship of prior trainees including K08 recipients. Dr. Simpson’s application of Dr. Holzbaur’s toolkit to epidermis provides a natural independence from her focus on neurodegeneration. Dr. Holzbaur’s guidance will be complemented by a committee of new and established investigators with expertise in cutaneous biology, intravital microscopy, and physician-scientist training. The K08 proposal includes training in novel imaging techniques, new exposure to in vivo models, and coursework in advanced/quantitative microscopy. Penn offers an outstanding Dermatology faculty with opportunities to collaborate as well as NIAMS P30-supported core facilities for keratinocyte culture and histology, providing an optimal environment to support Dr. Simpson as he transitions to begin an independent research program.

Project Narrative The epidermis forms the outermost portion of the skin and is made up of multiple layers of cells called keratinocytes, which function together as a barrier to resist dehydration and provide protection from environmental damage. While the inner keratinocyte layers need to maintain healthy organelles in order to continually regenerate the skin, the outer keratinocyte layers must degrade their organelles to form the compact cellular sheets that provide a water-tight seal. The proposed project will use advanced microscopy to determine how keratinocytes repair, recycle, and degrade organelles with the ultimate goal of augmenting these processes to improve our ability to treat skin barrier disorders and prevent damage due to aging and ultraviolet light.