CAREER: UNRAVELLING THE NOVEL ROLE OF ORGANELLE ION CHANNELS IN XENOPHAGY

The University Of Texas Rio Grande Valley, Edinburg TX

Investigators

Abstract

Xenophagy is a vital cellular process that animal cells use to eliminate invading pathogens. Immune cells fight these invaders, but new discoveries reveal that non-immune cells deploy xenophagy to eliminate these intruders. Xenophagy utilizes lysosomes, tiny organelles inside the cell that contain acidic ions like calcium to recycle old cell contents, but how these organelles help clear pathogens is poorly understood. This study will discover how lysosomes get rid of pathogens by focusing on ion channels that pass calcium into and out of cells to regulate lysosome functions. Investigating these ion channels will reveal novel approaches to enhance xenophagy and improve our body's natural defenses to fight illnesses and infections. This project provides educational and research opportunities for students at the University of Texas Rio Grande Valley (UTRGV). The Principal Investigator will promote hands-on research experiences and training opportunities for high school, undergraduate, and graduate students. Sophomore and junior students at UTRGV will have an exciting opportunity to take part in a 10-week summer internship program at prestigious medical institutions in Texas, to expand student knowledge and passion for cell physiology. In collaboration with UTRGV’s High Scholar program, the PI will transform the 9-week summer programs into year-long research experiences for high school students. To further improve research training for these students, an existing course will be refined to offer an advanced curriculum focused on cellular imaging. This proposed research will address the current lack of mechanistic understanding of xenophagy regulation by investigating the roles of key ion channels in the function of lysosomes in xenophagy. By using gastrointestinal cells as an animal cell model and Escherichia coli as the pathogen, this study aims to: 1) identify the molecular and cellular mechanisms governing lysosomal homeostasis when cells encounter E. coli invasion, and; 2) determine how ion channels facilitate the breakdown of internalized E. coli within lysosomes. Preliminary findings suggest that lysosomal calcium and potassium channels, along with reactive oxygen species (ROS) signaling, collectively play a crucial role in assisting cellular machinery in eliminating E. coli through xenophagy. This project takes a multi-disciplinary approach by combining ROS/calcium imaging, organelle electrophysiology, electron microscopy, and mouse models to investigate how ROS and lysosome ion channels connect to xenophagy initiation pathways to trigger E. coli clearance. The goal is to illuminate the intricate networks that govern these vital cellular processes for destroying pathogens. The research will also examine natural/synthetic modulators of lysosome ion channels and xenophagy pathways to gain valuable insights into how these compounds impact cell responses to bacterial invasion. Overall, this research will contribute to expanding our knowledge of how cells detect and respond to infections by optimizing lysosome synthesis and enhancing the function of xenophagy machinery in digesting internalized bacteria. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.