# Project 1  CaMKK2 a novel target to mitigate radiation induced injury of the hematopoietic system and the gastrointestinal tract

> **NIH NIH U19** · DUKE UNIVERSITY · 2021 · $461,664

## Abstract

In the event of a nuclear accident or a radiological attack, the exposure to ionizing radiation can
cause acute damage to radiosensitive tissues that have rapid turnover rates, including the
hematopoietic (H) system and gastrointestinal (GI) tract. After irradiation, an insufficient
regeneration of either the hematopoietic system and/or the GI tract can lead to death within a
few weeks, which is termed the acute radiation syndrome (ARS). Although significant progress
has been made to understand mechanisms underlying the ARS, no FDA approved therapy is
available to treat both the H-ARS and the GI-ARS when given at least 24 hours after irradiation.
At this time point, the majority of tissue stem/progenitor cells will already be dead. Therefore,
there is an urgent need to develop novel medical countermeasures (MCMs) that target master
regulators of tissue regeneration in response to radiation injury. The long-term goal of this
project is to develop a novel class of MCMs that mitigate both the H-ARS and GI-ARS by
targeting calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2). We have shown
that inhibition of CaMKK2 by genetic deletion or by the small molecule inhibitor STO-609 is
sufficient to stimulate hematopoietic regeneration and mitigate the H-ARS. Remarkably, our
preliminary data indicate that deletion of Camkk2 specifically in myeloid cells is sufficient to
facilitate blood cell formation following total body irradiation. More recently, we found that
deletion of Camkk2 also protected mice from the GI-ARS. Of note, outside the brain, the
expression of CaMKK2 is restricted to a small number of cell types, including macrophages and
epithelial tuft cells, which share the ability of tuning the regeneration rate of hematopoietic and
intestinal stem cells. Based on these findings, we hypothesize that CaMKK2 is an important
druggable target to regulate the behavior of hematopoietic and intestinal stem cell niches, and
blocking this enzyme 24 hours after irradiation will be sufficient to facilitate tissue regeneration
in response to radiation injury. We will test this hypothesis using sophisticated mouse models,
CaMKK2 inhibitor, along with primary bone marrow cells and intestinal organoids from human
donors. Using these combined approaches, we will define mechanism(s) by which CaMKK2
expressed in myeloid cells mitigate H-ARS, and will determine the impact of acute Camkk2 loss
in tuft cells after irradiation on the development of GI-ARS. By completing this grant, we expect
to gain new insight into the role of CaMKK2 in regulating both the H-ARS and GI-ARS. More
importantly, by more comprehensively understanding mechanism(s) underlying the effects of
CaMKK2 inhibition on mitigating the ARS, we will lay the foundation for approval of STO-609 as
a medical countermeasure against radiation under the FDA’s Animal Rule.

## Key facts

- **NIH application ID:** 10152504
- **Project number:** 5U19AI067798-17
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Nelson J. Chao
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $461,664
- **Award type:** 5
- **Project period:** 2005-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152504

## Citation

> US National Institutes of Health, RePORTER application 10152504, Project 1  CaMKK2 a novel target to mitigate radiation induced injury of the hematopoietic system and the gastrointestinal tract (5U19AI067798-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10152504. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*