# Uncovering the hidden universe of metabolite-specific T lymphocytes,using human multiorgan microphysiological systems.

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $409,375

## Abstract

PROJECT SUMMARY
Metabolic and inflammatory disorders such as autoimmune and neurodegenerative diseases are increasing at
alarming rates. Many of these are not tissue-specific occurrences but complex and often overlapping
pathologies of unknown origin for which no cure exists. Examples are concurring pathologies of the gut-liver
axis, such as inflammatory bowel disease and inflammatory pathologies of the liver.
The discovery of “unconventional” T lymphocytes and their ability to respond to non-peptide antigens, marks a
new area in the exploration of how migratory cells and immunometabolic networks shape the emergence of
autoimmune and metabolic diseases. These are comprised of a heterogeneous group of lymphocytes, such as
mucosa-associated invariant T cells, whose invariant TCR can recognize cellular and microbial metabolites via
presentation through the MHC-like receptor 1 (MR1). Emerging evidence suggest MR1-restricted T cells to be
implicated in a wide variety of disorders ranging from ulcerative colitis to type 1 diabetes, autoimmune hepatitis
and multiple sclerosis via TCR-specific and non-specific means.
However, lack of models relevant to human physiology represents a significant hurdle in our understanding of
how MR1-restricted T cells affect the host and diseases. We have developed an approach that utilizes multiorgan
human microphysiological models (MOMPS) of donor-matched tissues and unbiased systems biology tools to
gain granular insight into causal relationships between cellular crosstalk and immunometabolic illnesses. In order
to gain critical knowledge about the heterogeneity and functionality of MR1-restricted lymphocytes, we will
combine single-cell characterization of human MR1-restricted T cells across donor-matched tissues and
circulation, with mechanistic studies in a microphysiological model of the gut-liver axis. These MOMPS will be
used to systematically search for causal relationships between MR1-restricted lymphocytes, tissues, and
external factors by reconstructing donor tissue at various levels of complexity. Each level will be challenged via
predetermined inflammatory and metabolic perturbations. Multiomic observation of changes based on interaction
and perturbation at each degree of complexity will allow us to construct interaction networks that reveal causal
relationships among entities. With computational tools and resolution into molecular underpinnings of cellular
and tissue homeostasis, MOMPS represent a unique opportunity to systematically dissect how interactions at a
lower order inform new behavior at the macro scale within and between organ systems. While the gut-liver axis
will serve as a model in this proposal, the developed approach, together with fundamental biological insights into
MR1 expression by parenchymal tissue and function of MR1-restricted T cells, will be applicable to other organ
systems and a variety of pathologies. Our overarching goal is to identify tangible targets and new cell-based
appro...

## Key facts

- **NIH application ID:** 10847435
- **Project number:** 5R35GM146900-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Martin Trapecar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847435

## Citation

> US National Institutes of Health, RePORTER application 10847435, Uncovering the hidden universe of metabolite-specific T lymphocytes,using human multiorgan microphysiological systems. (5R35GM146900-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10847435. Licensed CC0.

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