# Intestinal tissue intrinsic mechanisms in regulation of GI GVHD

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $643,890

## Abstract

The overarching goal of this R01 is to develop non immunosuppressive strategies to prevent and treat
gastrointestinal (GI) GVHD, which remains a major cause of morbidity and mortality from allogeneic hematopoietic
cell transplantation (HCT). We have uncovered an exciting, previously unknown role for metabolic aberrations in
allo-reactive T cell target tissues, the intestinal epithelial cells (IECs) in regulating the severity of GI GVHD. Our
preliminary data identified a profound defect in mitochondrial complex II (MC II), specifically reduction of its
component, succinate dehydrogenase A (SDHA), in IECs that contributed to severity of GI GVHD. These studies
have identified a key role for SDHA in bulk IECs, which is made up of a number of distinct subsets. Emerging data
in the recent years suggest that quantitative loss of only a few key IEC subsets, specifically Lgr5+ intestinal stem
cell (ISCs) is a critical features of severe GI GVHD. But the ISC intrinsic pathways that are critical for their function
and maintenance remain unknown. Our new preliminary data demonstrate that the mitochondrial metabolic defect,
reduction of SDHA component of the mitochondrial complex II (MC II), in the bulk IECs, is observed in the ISC
subsets. In this project, we will build on these exciting and seminal preliminary observations and explore the role
of mitochondrial metabolic and bioenergetics functions in the biology of ISCs and its contribution to mitigating the
severity of GI GVHD. Specifically, we will test the central hypothesis that host Lgr5+ ISCs cell autonomous
deficiency of mitochondrial complex II component, SDHA amplifies GI GVHD. The specific aims are:
Specific Aim (SA) 1: To determine the functional relevance of mitochondrial complex II component (SDHA) in
host Lgr5+ ISCs to GI GVHD.
SA 2: Determine the impact of mitochondrial complex II SDHA deficiency on the biology of Lgr5+ ISC.
If successful, our proposal will provide seminal insights into fundamental biology of ISCs, provide novel targets to
mitigate T cell mediated target organ damage without adding more immune suppression and thus have potential
implications not only for allo-HCT but also for autoimmunity, solid organ transplantation and T cell mediated
therapies.

## Key facts

- **NIH application ID:** 10865043
- **Project number:** 5R01AI165563-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** PAVAN REDDY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $643,890
- **Award type:** 5
- **Project period:** 2022-06-13 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865043

## Citation

> US National Institutes of Health, RePORTER application 10865043, Intestinal tissue intrinsic mechanisms in regulation of GI GVHD (5R01AI165563-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10865043. Licensed CC0.

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