Metabolic Control of Membrane Lysis

Project Summary Regulated cell death is essential for immune defense, development, and maintaining tissue homeostasis. While apoptosis removes damaged cells without causing inflammation, lytic cell death pathways such as pyroptosis and necroptosis may lead to excessive inflammation, contributing to chronic diseases and autoimmunity. Recent discoveries suggest that metabolism not only fuels cellular functions but also actively regulates the decision between survival and cell death. This project aims to explore how metabolic pathways control the transition between life and death, particularly focusing on comparing the lytic cell death program pyroptosis to the non-lytic cell death program apoptosis. Our research will investigate key metabolic regulators that influence cell death executioners that control membrane lysis including gasdermin D (GSDMD) and NINJ1. We will employ cutting-edge genetic and synthetic biology approaches, including forward and reverse genetics with CRISPR/Cas9, metabolic profiling, and engineered cell models, to uncover how metabolic signals determine whether cells commit to viability, pyroptosis, or apoptosis. Our work will also explore how metabolites released during cell death communicate with neighboring immune cells, shaping inflammatory responses and immune activation in vaccination, local infection, and systemic sepsis. By mapping the metabolic checkpoints that dictate cell fate, we aim to identify new therapeutic targets for modulating cell death and inflammation. These mechanisms will inform precision treatments to prevent excessive inflammation in autoimmune diseases, enhance immune responses in infections, and overcome chemotherapy resistance in cancer. The integration of synthetic biology, genetics, and chemical biology makes this a highly innovative and interdisciplinary project with significant implications for foundational research and human health. Upon completion, we expect to provide new strategies to control cell death and improve therapies for conditions where dysregulated cell death plays a pivotal role.