# Lysosome Homeostasis and Microbicidal Mechanisms in Innate Immunity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $612,953

## Abstract

ABSTRACT
!
Recent advances to decode the genetics underlying inflammatory bowel disease (IBD) have led to the
discovery of numerous IBD-associated genetic variants in the human genome. Our work studying these
variants using genomics, mouse models, systems biology, and human patient samples has revealed the
central role of autophagy and intracellular antimicrobial defense in the pathogenesis of IBD. In particular,
characterization of IBD-associated I231L variant in the G protein-coupled receptor GPR65 revealed a key
role of GPR65 as an environmental sensor that maintains lysosomal pH and function. Regulatory
mechanisms that maintain lysosome homeostasis are critical in phagocytes such as macrophages, which
require a highly developed lysosome network for delivery of microbicidal machinery to the phagosome.
Recently, we have found that GPR65 interacts with the transcription factor, TFEB, that controls lysosome
biogenesis. Here, we investigate the mechanisms by which GPR65 acts as a sensor, interpreting
environmental cues and eliciting adaptive responses to maintain lysosomal homeostasis through TFEB. In
Aim 1, we examine the role of GPR65 in controlling lysosome homeostasis through signaling intermediates
and TFEB transcriptional activity. In Aim 2, we investigate the mechanisms by which impaired GPR65
signaling, and particularly the GPR65 I231L variant, results in colitis and pathogen susceptibility. In Aim 3,
we will define how endogenous metabolites regulate TFEB activity. These research aims will advance our
understanding of how metabolic sensors and lysosomal homeostasis mediate intracellular pathogen
defense and could reveal a widespread role for lysosome biology in innate immunity.

## Key facts

- **NIH application ID:** 9879743
- **Project number:** 5R01DK117263-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ramnik J Xavier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,953
- **Award type:** 5
- **Project period:** 2018-05-11 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879743

## Citation

> US National Institutes of Health, RePORTER application 9879743, Lysosome Homeostasis and Microbicidal Mechanisms in Innate Immunity (5R01DK117263-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879743. Licensed CC0.

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