# THE FUNCTION AND REGULATION OF HISTIDINE DECARBOXYLASE IN GUT INFLAMMATION

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $360,000

## Abstract

SUMMARY
Bone marrow-derived myeloid cells are a heterogeneous group of leukocytes that play key roles in response to
intestinal injury. We have previously reported myeloid cell differentiation is regulated by histamine, produced by
the enzyme histidine decarboxylase (HDC), which is expressed in a large subset of immature myeloid cells that
contribute to colorectal cancer. We have now discovered that HDC also marks a unique subset of myeloid-
biased hematopoietic stem cells (MB-HSC) that are maintained in quiescence by histamine signaling from
myeloid daughter cells. In response to injury or cancer, this HDC+ myeloid lineage is mobilized from the BM,
thus reducing histamine and activating the MB-HSC to produce more progeny that contribute to epithelial
regeneration and immunosuppression. Insufficient histamine signaling leads to overexuberant inflammatory
responses, HSC exhaustion, and increased lethality following DSS colitis. Preliminary data from our lab
indicate that HDC+ myeloid cells are a major source of Wnts and PGE2, highly express the immune
checkpoint ligand PD-L1, and in the setting of carcinogenesis constitute the major myeloid suppressor
population. Thus, we hypothesize that HDC+ HSC plays a unique role in intestinal regeneration and is
regulated by histamine-secreting myeloid cells in the ISC niche. We propose 3 specific aims. (1). Does
excessive loss of bone marrow histamine production contribute to HSC exhaustion and hyper-inflammatory
response in acute, severe colitis? We will use DTA ablation of HDC+ myeloid cells, HDC knockout mice and
DSS colitis to examine the impact on HSCs during intestinal injury. (2). Is the HDC+ myeloid lineage important
for intestinal regeneration? We will examine the effects of DTA ablation of HDC+ myeloid cells, and
conditional knockout of Porcupine and COX-2, to determine their contribution to ISCs and intestinal
regeneration. (3). Is the HDC+ myeloid lineage the principal source of myeloid suppressors that contribute to
early intestinal preneoplasia? We will use the AOM/DSS model in combination with bone marrow transplants,
adoptive transfer, DTA ablation and CD8+ T cell depletion to determine the role of HDC+ cells in CRC and
whether this depends on inhibition of CD8+ T cells.

## Key facts

- **NIH application ID:** 9975165
- **Project number:** 5R01DK048077-24
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Timothy Cragin Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,000
- **Award type:** 5
- **Project period:** 1995-01-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975165

## Citation

> US National Institutes of Health, RePORTER application 9975165, THE FUNCTION AND REGULATION OF HISTIDINE DECARBOXYLASE IN GUT INFLAMMATION (5R01DK048077-24). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9975165. Licensed CC0.

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