# Molecular characterization of the role for metabolites in immune cell differentiation

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $439,548

## Abstract

Abstract
The dynamic regulation of metabolic states plays an active role in cellular differentiation decisions, and this
occurs throughout mammalian development. The conservation of these processes in different species,
developmental settings, and immune cell types suggests metabolism influences common mechanistic events
needed for differentiation decisions in diverse cellular backgrounds. However, the interpretation of these
conserved mechanisms must have a component of cell-type specificity to properly regulate the genome to
promote appropriate differentiation in individual cellular settings. Therefore, it is important to define the
conserved and cell-type specific mechanistic principles to understand how dietary and metabolic interventions
influence immune cell differentiation in the context of healthy and disease states. In the previous funding cycle
of this grant, we identified a role for alpha-ketoglutarate (aKG) in regulating the IL-2-sensitive gene program in
T cells. Mechanistically, aKG-sensitive events enhanced the association of CTCF with a subset of sites in
CD4+ T cells, and together with studies in cancer cells, the data indicated this overall activity is conserved in
diverse cell-types. The data also suggested these events are interpreted in a cell-type specific manner,
potentially based on the enhancer landscape of the cell. In this grant, we will extend these findings to address
how aKG-sensitive CTCF sites are selected, and whether there are any cell-type dependent mechanisms
selecting these sites. We will also define whether downstream mechanisms, such as enhancer activity, have
sensitivity to metabolic states. In this context, we will address whether the enhancer landscape is regulated by
short chain fatty acids such as butyrate and acetate. We will also define which aspects of metabolite-sensitive
mechanisms are conserved between species, and how variation between the mouse and human genome
influences the interpretation of conserved and cell-type specific events. Information gained in these studies will
be critical for predicting the role for metabolic and dietary interventions in the treatment of immunological
diseases and in promoting effective immune responses to infectious diseases.

## Key facts

- **NIH application ID:** 10599676
- **Project number:** 2R01AI061061-17A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Amy Susan Weinmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $439,548
- **Award type:** 2
- **Project period:** 2004-06-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599676

## Citation

> US National Institutes of Health, RePORTER application 10599676, Molecular characterization of the role for metabolites in immune cell differentiation (2R01AI061061-17A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10599676. Licensed CC0.

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