PROJECT SUMMARY / ABSTRACT Erythropoietic protoporphyria (EPP) is caused by pathogenic variants of the last enzyme of heme biosynthesis, which produces life-long, painful cutaneous sensitivity to light. In EPP, the light-sensitive molecule protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in the plasma and the liver. In addition to photosensitivity, EPP can result in anemia, gallstones, and chronic liver disease, and 2-5% patients develop rapidly progressive cholestatic liver failure that is fatal without liver transplantation. The approval of new therapeutics in EPP has been greatly hindered by the lack of quantitative clinical trial endpoints. While the Food and Drug Administration recently approved one therapy that helps to prevent EPP-related photosensitivity, no disease-modifying therapy is available for EPP. The objective of this study is to develop methods to quantitatively measure light sensitivity in EPP and to understand the genetic basis for differences in light sensitivity among patients. Light sensitivity will be measured by the combination of light dosimetry, transcutaneous PPIX fluorometry, and daily text symptom surveys. The genetic basis for differences in light sensitivity among patients will be characterized by performing whole exome sequencing and a genotyping array in EPP patients possessing the same FECH genotype and large discordances in light sensitivity and/or PPIX level. First, polygenic risk scores that were developed in large datasets will be applied to the genetic data of this selected patient population. Next, disease-modifying coding variants will be identified in the exome sequences, followed by in vitro validation. This project could lead to (1) methods to predict and prevent photosensitivity in EPP thus improving quality of life, (2) quantitative endpoints for clinical trials facilitating the approval of new therapies, and (3) a better understanding of the modulators of light sensitivity in EPP, which could lead to novel therapeutics. This research will be performed by Dr. Amy Dickey, an Instructor of Medicine at Harvard Medical School and Massachusetts General Hospital. She will receive first-rate training in statistics, epidemiology, clinical trial design, and genetic analysis. Furthermore, she will be exceptionally mentored by Dr. David Christiani, an expert in genetic and environmental epidemiology, and co-mentored by Dr. Mark Fleming, an expert in heme metabolism and rare disease genetic analysis. She will perform her research in a world- renowned academic center with all required resources available to her. Dr. Dickey's goal is to become a physician-scientist in patient-oriented porphyria research. This K23 award will provide her with the training and mentorship to achieve independence and apply for her first R01.