# Impact of Infection and Inflammation on Primitive Hematopoiesis

> **NIH NIH R35** · BAYLOR COLLEGE OF MEDICINE · 2024 · $844,190

## Abstract

Project Summary/Abstract
Hematopoietic stem cells (HSCs) in the bone marrow are responsible for the regulated production of about ten
billion blood cells per day. Inflammation plays a key role in HSC function, promoting increased production of
immune cells during conditions of stress or infection. However, Dr. King’s prior work has shown that prolonged
exposure to interferon gamma, induced during chronic mycobacterial infections, alters HSC self-renewal and
differentiation, ultimately leading to HSC depletion and pancytopenia. This discovery spawned an explosion in
research into the connections between inflammation and primitive hematopoiesis and the role of inflammation
in bone marrow failure syndromes, hematologic malignancies, and age-associated impaired immunity. Despite
its disease relevance, fundamental questions remain about the mechanisms by which inflammation releases
HSCs from quiescence and promotes differentiation, and the hematologic and immunologic consequences of
these changes. The proposed research program builds upon the PI’s productive research track record to
delineate the molecular, transcriptional, and epigenetic mechanisms by which inflammation regulates primitive
hematopoiesis. Dr. King has identified key molecular mediators of inflammation-induced HSC differentiation
including the transcription factor Batf2 and the cell surface adhesin Bst2, highlighting how both cell intrinsic
transcriptional changes and cell extrinsic alterations in cell-cell interactions contribute to altered HSC activity
upon inflammation. Furthermore, Dr. King has extrapolated this work to show how a mutation in the epigenetic
modifier Dnmt3a impairs inflammation-induced differentiation of HSCs and thereby contributes to clonal
hematopoiesis, a widespread phenomenon linked to heart disease, stroke, and increased mortality in the
elderly. Building on this groundbreaking work, the proposed research program is divided into three projects.
The first project will delineate the mechanism of action of Batf2 and Bst2 in inflammation-mediated HSC
differentiation. These mechanistic studies will provide potential therapeutic targets to preserve HSC function in
the setting of chronic inflammation. The second project will quantify the impact of HSC differentiation on clonal
competition in order to provide critical insight into infection and inflammation as an environmental contributor to
clonal hematopoiesis, which is a risk factor for leukemia and cardiovascular disease. Finally, the third project
will ascertain the importance of inflammation-induced transcription and epigenetic changes in HSCs to
immunity. These studies will elucidate how inflammatory regulation of HSCs contributes to formation and
function of immune effector cells. Collectively, the proposed research program defines the impact of
inflammatory cytokine signaling on HSCs, their longevity, and their ability to maintain a healthy blood and
immune system over time. The long-term goal of these studie...

## Key facts

- **NIH application ID:** 10875576
- **Project number:** 5R35HL155672-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Katherine Yudeh King
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $844,190
- **Award type:** 5
- **Project period:** 2021-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875576

## Citation

> US National Institutes of Health, RePORTER application 10875576, Impact of Infection and Inflammation on Primitive Hematopoiesis (5R35HL155672-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10875576. Licensed CC0.

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