# New approaches to combat CNS inflammation in Veterans: Targeting a metabolic enzyme in demyelinating disease

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Multiple sclerosis (MS) is a debilitating demyelinating disease of the central nervous system (CNS) that
affects approximately 2.5 million people worldwide. US military personnel are at special risk to develop MS:
the incidence rate in the US military population (12.9 per 100,000 person-years) is 1.7x higher than the civilian
population, and 3x higher than the global population. Experimental autoimmune encephalomyelitis (EAE) is a
widely studied animal model that shares many features of human MS. Tissue injury in EAE and MS is caused
by inflammatory leukocytes that enter the CNS and destroy myelin. CNS-infiltrating, myelin-reactive CD4+ T
cells play key roles in the pathology of MS. Although a number of MS treatments are available, due to the
heterogeneity of the MS disease process, individual patient responses, and medication toxicities, there is a
substantial unmet clinical need for improved therapeutics.
 T cell differentiation and function is profoundly affected by the engagement of metabolic pathways retinoid
processing. Diacylglycerol O-acyltransferase-1 (DGAT1) is a metabolic enzyme that can catalyze the
synthesis of triglycerides (TG, via DGAT activity), and retinyl esters (RE, via acyl CoA:retinol acyltransferase
(ARAT) activity). Little is known regarding the role of DGAT1 in T cell biology. Our preliminary studies suggest
that DGAT1 is selectively upregulated in activated mouse CD4+ T cells both in vitro and in vivo during EAE.
DGAT1 is selectively expressed in brain lesions and CD4+ blood T cells obtained from MS patients. DGAT1
KO mice are protected against EAE, and DGAT1 pharmaco-inhibition suppresses EAE. Based on our
preliminary data and the importance of retinoid metabolism in governing T cell differentiation and function, we
hypothesize that T cell-expressed DGAT1 plays a key role in regulating pathogenic T cell activity in
autoimmune demyelinating disease.
 In Aim 1 we will investigate the translational utility of targeting DGAT1 with small molecule antagonists to
treat demyelinating disease. We will test the hypothesis that human blood CD4+ T cells express DGAT1 and
contain DGAT/ARAT activity, and that DGAT1 regulates Treg and Th17 differentiation and function. We will
also test the hypothesis that DGAT1 inhibitors administered after disease onset will reverse EAE progression
and prevent relapse. Notably, small-molecule DGAT1 inhibitors are already being tested in clinical trials for
treatment of obesity-associated diseases. Thus the studies in Aim 1 may uncover new MS-specific
applications for existing drugs that have already cleared Phase I safety studies. In Aim 2 we propose to define
the role of DGAT1 in CD4+ effector T cell formation and function. Using in vitro polarized CD4+ T cells, we will
define DGAT1 expression and ARAT activity in mouse Treg and Th17 cells. Using naive T cells from WT and
DGAT1 KO mice, we will define the role of DGAT1 in Treg and Th17 differentiation and function. To facilitate
the study of DGAT1 ...

## Key facts

- **NIH application ID:** 9815320
- **Project number:** 5I01BX004115-02
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** BRIAN A. ZABEL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815320

## Citation

> US National Institutes of Health, RePORTER application 9815320, New approaches to combat CNS inflammation in Veterans: Targeting a metabolic enzyme in demyelinating disease (5I01BX004115-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815320. Licensed CC0.

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