Endolysosomal physiology of myeloid phagocytes

The National Institute of General Medical Sciences awarded the University of Virginia $441,474 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate how ion channels orchestrate endolysosomal system functions in myeloid phagocytes.

The research pursues three complementary directions: characterizing how M7VS (specialized TRPM7-containing vesicles) drive phagosome maturation and endolysosomal homeostasis; dissecting the dual channel-kinase functions of TRPM7 through advanced electrophysiology and proteomics; and mapping tissue-specific variations in endolysosomal ion channels across diverse myeloid phagocytes, including tissue-resident macrophages such as microglia and Kupffer cells. The work builds on recent discoveries identifying TRPM7 as a major regulator of endolysosomal function that provides essential counterion conductance for V-ATPase-driven acidification and plays a crucial role in viral entry and efferocytosis. The investigator will employ organellar patch-clamp electrophysiology, advanced imaging, and proteomics approaches. The fundamental knowledge generated has potential application to therapeutic strategies for diseases involving dysregulated endolysosomal function, including chronic infections, inflammatory conditions, and cancer.

Performance occurs in Charlottesville, Virginia, with a period of performance from August 1, 2026, through May 31, 2031. The assistance type is a Project Grant.

Abstract

Myeloid phagocytes, including tissue-resident macrophages, are essential guardians of tissue homeostasis and immune defense. Their diverse functions depend critically on the endolysosomal system - a dynamic network of vesicles that help degrade pathogens, process antigens, and maintain tissue homeostasis through clearance of dead cells. This project investigates how ION channels orchestrate the complex functions of the endolysosomal system in myeloid phagocytes. Our research builds on our recent discoveries about TRPM7, an unusual ION channel-kinase fusion protein that serves as a major regulator of endolysosomal function. We found that TRPM7 provides essential counterion conductance for v-atpase-driven acidification and identified specialized TRPM7- containing vesicles (M7VS) that deliver critical machinery for phagosome acidification. These discoveries revealed TRPM7's crucial role in viral entry and efferocytosis. The research program pursues three complementary directions: (1) characterizing how M7VS drive phagosome maturation and endolysosomal homeostasis, (2) dissecting the dual channel-kinase functions of TRPM7 through advanced electrophysiology and proteomics, and (3) mapping tissue-specific variations in endolysosomal ION channels across diverse myeloid phagocytes. Given that tissue-resident macrophages face distinct environmental challenges - from microglia in the brain to kupffer cells in the liver - understanding their specific ION channel requirements is crucial. We will combine sophisticated approaches including organellar patch-clamp, advanced imaging, and proteomics to illuminate how ION channels coordinate the complex functions of the endolysosomal system. This fundamental knowledge has the potential to inform new therapeutic strategies for diseases involving dysregulated endolysosomal function, including chronic infections, inflammatory conditions, and cancer.