# Mechanisms of reticulophagy and ER stress mitigation in epidermis

> **NIH NIH R03** · UNIVERSITY OF WASHINGTON · 2024 · $88,250

## Abstract

Project Summary/Abstract
 The epidermis forms a multi-layered epithelium that serves as a protective shield for the body, preventing
dehydration and pathogen invasion. Its principal cellular constituents, keratinocytes, continually regenerate the
cutaneous barrier via a specialized form of differentiation as they move outward in the tissue. At the end of
their life in the skin’s outermost layers, keratinocytes initiate a cellular remodeling program called cornification
in which they eliminate their organelles to form flattened, keratinized cells. The importance of this process is
underscored by many disorders of cornification linked to defective keratinocyte maturation. Despite the advent
of biologic treatments for inflammatory skin diseases, development of similar targeted therapies for epidermal
barrier dysfunction has been limited by an incomplete understanding of the pathways driving keratinocyte
differentiation. The proposed aims address this knowledge gap by applying advanced microscopy, gene
editing, and optogenetics to define the mechanisms mediating organelle degradation in human epidermis.
 This proposal builds on the PI’s K08 project, which found that cornifying keratinocytes induce autophagy, a
lysosomal degradation pathway, to break down organelles. The K08-funded work showed that differentiating
keratinocytes upregulate an autophagy receptor, NIX, which marked mitochondria and instructed cells in the
upper tissue layers to break down these organelles, a step that was essential for epidermal maturation. Our
planned experiments will expand the K08 project scope to include the endoplasmic reticulum (ER), testing the
hypothesis that keratinocytes utilize distinct autophagy receptors to orchestrate breakdown of the ER (called
reticulophagy). Aim 1 will determine how reticulophagy drives programmed ER degradation during cornification
and Aim 2 will assess if reticulophagy mitigates damage from ER stress in keratinocytes. Preliminary studies
identified candidate receptors that initiate reticulophagy in either a constitutive manner during cornification or
upon organelle injury due to ER stress. We will use gain- and loss-of-function approaches in organotypic skin
to determine the role of these receptors in directing epidermal morphogenesis and mitigating ER stress. As
well, we will leverage live biosensor imaging and optogenetic tools to define how reticulophagy alters signaling
mediators that control keratinocyte differentiation, including calcium and reactive oxygen species. Results from
the planned work promise to identify novel strategies for normalizing epidermal differentiation in disorders of
cornification but also for repairing barrier dysfunction in common diseases like atopic dermatitis and psoriasis.
 Augmenting the investment by the University of Washington to ensure his success as a physician-scientist,
R03 funding will advance the PI’s career development and position him to compete for R01-level funding as he
transitions to an...

## Key facts

- **NIH application ID:** 10888996
- **Project number:** 5R03AR082896-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Cory L Simpson
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $88,250
- **Award type:** 5
- **Project period:** 2023-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888996

## Citation

> US National Institutes of Health, RePORTER application 10888996, Mechanisms of reticulophagy and ER stress mitigation in epidermis (5R03AR082896-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10888996. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*