# Project 1: HDAC inhibition and GVHD

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $327,440

## Abstract

PROJECT 1 SUMMARY/ABSTRACT
Intestinal epithelial cell (IEC) damage by the donor alloreactive T cells causes gastrointestinal (GI)
graft-versus-host disease (GVHD) allogeneic bone marrow transplantation (BMT). The host IEC
intrinsic mechanisms that enhance their resistance to the damage by the donor alloreactive T cells
might have therapeutic potential in GVHD. IEC homeostasis and resistance depends on complex
interactions between the metabolic energy substrates and the regulation of transcription and epigenetic
chromatin modifications such as histone acetylation. But the mechanisms of IEC resistance and the
relevance of metabolic regulation of histone acetylation in reducing the severity of GVHD has
heretofore not been studied. In the current cycle, we have demonstrated and published that epigenetic
regulation by systemic administration of histone deacetylase inhibitors (HDACi) regulates experimental
GVHD and successfully translated it into a proof of concept human trial for prevention of clinical GVHD.
Preliminary data generated during this cycle also demonstrate a significant alteration in the IEC energy
substrates that are derived from microbial metabolites, specifically the essential short chain fatty acids
(SCFA), such as butyrate in the intestinal tissues after allogeneic BMT. Preliminary data also show that
butyrate, which is a known HDACi, enhances histone acetylation, modulates IECs sensitivity damage,
and regulates GVHD in vivo. But the pathways of sensing and the mechanisms underlying the
butyrate-mediated effects are not known. Therefore, in this proposal, we will build on these exciting
and novel preliminary observations to explore the interplay between microbial metabolite and the HDAC
inhibitor, butyrate, and its effects on epigenomic alterations of the IECs in reducing GI GVHD.
Specifically, we will test the central premise that endogenous intestinal microbial metabolite, butyrate,
promotes acetylation of intestinal IECs and negatively regulates GI GVHD.
We will explore this premise in the following three specific aims:
1. To determine the pathways of sensing microbial metabolite butyrate by the intestinal
epithelial cells (IECs) and its impact on GVHD. In this SA we will test the hypothesis that chemo-
sensing of the microbial metabolite butyrate by the G-protein coupled receptor 43 (GPCR43) on the
intestinal epithelial cells (IECs) will reduce GVHD.
2. To analyze the molecular mechanisms for butyrate mediated resistance of intestinal
epithelial cells (IECs) after allogeneic BMT. In this SA we will explore the hypothesis that the cell
intrinsic oxidative metabolic state of IECs is critical for the butyrate mediated histone acetylation
and epigenetic regulation of IECs resistance against damage after allogeneic.
3. To determine the impact of butyrate administration on GVL. In this SA we will test the
hypothesis that administration of butyrate will mitigate inflammation and GVHD but retain sufficient
GVL responses.

## Key facts

- **NIH application ID:** 10006009
- **Project number:** 5P01CA039542-32
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** PAVAN REDDY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $327,440
- **Award type:** 5
- **Project period:** 1997-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006009

## Citation

> US National Institutes of Health, RePORTER application 10006009, Project 1: HDAC inhibition and GVHD (5P01CA039542-32). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006009. Licensed CC0.

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