Mechanisms of Lysosomal Resilience, Repair and Removal

SUMMARY Lysosomes are central players in cellular catabolism that play a pivotal role in regulating metabolism and signaling. Cellular and environmental stressors that damage the lysosomal membrane compromise organelle function and release toxic content into the cytoplasm that ultimately drives cell death. Building on our discovery that the ESCRT machinery is rapidly deployed to repair lysosomal membrane damage, there has been much interest in defining how cells sense acute changes in membrane structure and organization to coordinate among a growing array of restorative responses. Our goals over the coming five years will address key questions about how local membrane remodeling and reinforcement by ESCRTs integrate with changes in lipid delivery and cholesterol content to maintain integrity, how individual components of the ESCRT machinery contribute to resilience and repair, and how cells recognize unsalvageable lysosomes for removal. Using cell- biological, biochemical, and biophysical approaches, we will integrate studies of individual stress responses with a unified understanding of lysosomal membrane homeostasis. Project Number: 1R35GM163790-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Phyllis Hanson | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $425,916 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - D Study Section[MRAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11331039