Brittany White-Matthieu, Ph.D
Regulated cell death (RCD) is a fundamental biological process programed to occur and facilitate the removal of dysfunctional cells and tissue during development and infection. Excessive cell death results in inflammation and neurodegeneration, while diseases including cancer and autoimmune disorders modulate RCD mechanisms and their associated metabolites to evade elimination. The significance of RCD in human health has resulted in the development of treatments designed to promote or prevent cell destruction, making methods to further characterize RCD pathways critical for the development of novel therapeutic modalities. The long-term goal of the research described in this proposal is to expand our knowledge of RCD mechanisms from the perspective of cellular membranes, the biological structures that define individual cell death pathways.
In this proposed CIBBR COBRE Pilot Project, our research will be advanced towards this goal following experiments proposed in Aim #1. Our approach leverages strategies to label phosphatidylcholine (PC), an abundant phospholipid found in all organelle membranes, to facilitate analysis of membrane-biomolecule interactions. Specifically, we will evaluate membrane-anchored activity-based sensors for ROS including hydrogen peroxide, and Fe2+, a molecular driver and catalyst for ROS production, as they are produced in a cellular environment. ROS have been implicated in several RCD mechanisms where they rapidly oxidize nearby biomolecules including lipids and proteins within membranes. The broad reactivity of ROS coupled with their short biological lifetimes makes our approach essential for the analysis of ROS produced at cellular membranes where they exert cytotoxic effects during RCD. Assessment of probe optical properties and stability in solution and in live-cells will enable the development of multicolor imaging experiments to evaluate the cooperative production of hydrogen peroxide and Fe2+. Application of our method to models of ferroptosis will unveil organelle-specific production of ROS implicated in this pathway and establish feasibility of our method for the analysis of RCD. Insights gained from this research will define how cellular membranes influence the execution of specific forms of RCD, advancing mechanistic understanding of these pathways and guiding development of novel therapeutics.
Regulated cell death (RCD) pathways have emerged as viable targets for the treatment of human diseases. This research seeks to address critical gaps in knowledge surrounding RCD by defining cellular membranes as modulators of these pathways towards the identification of novel therapeutic targets.
