# Chemical, Structural and Cell-Signaling Interrogation of 15-Prostanglandin Dehydrogenase in Tissue Repair and Regeneration

> **NIH NIH RM1** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $94,538

## Abstract

Abstract. Prostaglandin E2 (PGE2) regulates tissue growth and repair in multiple organs. A conserved
mechanism of synthesis and degradation modulates PGE2 levels in response to trauma, inflammation and
disease. In particular, the enzyme 15-prostaglandin dehydrogenase (15-PGDH) is the main PGE2-degrading
enzyme and therefore a key regulator of tissue repair and regeneration. 15-PGDH is an attractive drug target
for diseases characterized by tissue damage. Our team successfully developed the first small molecule
inhibitors of 15-PGDH with in vivo activities. In rodents, our inhibitors 1) accelerate recovery following bone
marrow transplantation, 2) accelerate recovery from, or prevent, ulcerative colitis, 3) accelerate regrowth of
liver tissue following partial hepatectomy, 4) ameliorate pulmonary fibrosis in a bleomycin-induced disease
model, 5) enhance survival of new hippocampal neurons in adult mice, and 6) preserve cognitive function and
minimize neuronal damage in mice following traumatic brain injury. Independent reports have described
beneficial effects of 15-PGDH inhibition in models of renal disease and pulmonary fibrosis.
We now propose a collaborative chemical, structural and cell-signaling interrogation of the role and activity of
15-PGDH. Our expertise includes medicinal chemistry, biochemistry, neuroscience, pharmacology, and
structural biology. In Aim 1, we will define and exploit the structural basis for inhibition of 15-PGDH by small
molecules. This aims builds on the first cryoEM structure (2.3 Å resolution) of 15-PGDH and two unrelated
scaffolds of low-nM inhibitors of 15-PGDH. Proposed research aims to solve the structure of 15-PGDH in
complex with new small molecule inhibitors or substrate. Computational approaches will be employed to
interrogate substrate/inhibitor binding and the enzymatic mechanism. In Aim 2, we will define the cellular,
protein and cytokine signaling networks that are regulated by 15-PGDH and that are engaged by 15-PGDH
inhibitors to potentiate tissue regeneration and repair. The foundation of this aim includes the first
demonstration of 15-PGDH activity in the brain, the identification of macrophages and microglia as major
reservoirs of 15-PGDH expression in peripheral tissues and brain, respectively, and the discovery of cell and
cytokine networks that respond to inhibiting 15-PGDH. We now propose to use single-cell RNA sequencing to
determine the cell types that express 15-PGDH. Similar approaches will identify the cell-signaling network of
induced cytokines and the cell types activated to express them. These studies will be performed in mice
recovering from injury that have been treated with 15-PGDH inhibitors, along with appropriate controls. Finally,
we will engineer macrophage- and microglia-targeted 15-PGDH knockouts to define the role of 15-PGDH
expression in macrophages and microglia in mediating a conserved, cross-tissue response to PGE2 and 15-
PGDH inhibitors. This data set will provide a foun...

## Key facts

- **NIH application ID:** 11095070
- **Project number:** 3RM1GM142002-04S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** SANFORD D. MARKOWITZ
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $94,538
- **Award type:** 3
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11095070

## Citation

> US National Institutes of Health, RePORTER application 11095070, Chemical, Structural and Cell-Signaling Interrogation of 15-Prostanglandin Dehydrogenase in Tissue Repair and Regeneration (3RM1GM142002-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11095070. Licensed CC0.

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