# Towards Improving Bone Marrow Transplantation via Inhibition of 15-PGDH

> **NIH NIH R00** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $249,000

## Abstract

Project Summary:
Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic
malignancies. However, a potentially fatal complication of HST is the high risk of infection and bleeding recipients
are exposed to during the up to 4 weeks while awaiting regeneration of peripheral blood neutrophils and platelets.
I and collaborators published in 2015 in Science the discovery of a small molecule, SW033291, that potently
inhibits the prostaglandin degrading enzyme 15-PGDH and markedly speeds recovery from HST. As co-first
author, I led studies that showed that treating with SW033291 during murine HST enhances transplanted stem
cell homing to the bone marrow niche; markedly accelerates recoveries of neutrophils, platelets, and
erythrocytes; and increases the effective dose of a bone marrow graft by 5-fold. I showed these effects are
mediated by increased bone marrow PGE2, which acts on EP2 and EP4 PGE2 receptors to induce key
hematopoietic cytokines, SCF and CXCL12, in bone marrow stromal cells. In this application I now propose
elucidate the full cellular and signaling mediators of SW033291's effect on HST and to examine the interaction
of SW033291 with G-CSF, the clinical standard of care for stimulating hematopoietic recovery after human HST.
I will first comprehensively identify the molecular mediators of SW033291 effect (using RNA-seq) and identify
the bone marrow cells in which these mediators are induced and act (e.g. identifying the novel 15-PGDH positive
bone marrow cell that is first targeted by SW033291 and then the downstream cells in which SCF and CXCL12
are markedly induced). I will second interrogate the in vivo function of candidate mediators of SW033291 effect,
first by testing the ability of this drug to potentiate HST when candidate SW033291 mediators (e.g. 15-PGDH,
CXCL12, SCF, plus two new candidate mediators CXCL4 and CXCL7) are genetically deleted from both donor
mouse stem cells and recipient mouse bone marrow stroma. I will further map the differential effects of these
mediators on hematopoietic stem cells versus bone marrow stromal cells by examining the ability of SW033291
to potentiate HST when candidate mediators are selectively deleted only in donor HSCs or only in recipient bone
marrow stromal cells. Using these models I will further dissect each mediator's role at each of three successive
stages of SW033291 effect that are: i) potentiating homing of donor HSCs to the recipient marrow; ii) inducing
hematopoietic cytokines in the marrow HSC niche; iii) potentiating stem cell generation of daughter cells. Third,
I will examine the interaction of SW033291 with G-CSF, the standard of care used to augment neutrophil
recovery in human HSC, following up preliminary data that shows an additive to synergistic effect of SW033291
combined with G-CSF, and characterizing the mechanism of this synergy through identification of target changes
in the transcriptome and phosphoproteome of selected bone m...

## Key facts

- **NIH application ID:** 10044072
- **Project number:** 4R00HL135740-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Amar Desai
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2017-08-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044072

## Citation

> US National Institutes of Health, RePORTER application 10044072, Towards Improving Bone Marrow Transplantation via Inhibition of 15-PGDH (4R00HL135740-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10044072. Licensed CC0.

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