# The NFkB System in Dendritic Cells

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $415,163

## Abstract

Project Summary/Abstract
Dendritic cells (DCs) play key roles in targeting immune responses to pathogens, both by functioning as
antigen presenting cells and by secreting potent innate immune and inflammatory cytokines. They differentiate
from hematopoietic stem cells found in the bone marrow into multiple subtypes that have more
inflammatory/adaptive immune or more innate immune functions. Misregulation of these differentiation
processes is the root cause of myeloproliferative disorders (MPD) including acute myeloid leukemia (AML),
and the inflammatory disease Langerhans Cell Histiocytosis (LCH). These differentiation processes may be
recapitulated ex vivo with key myeloid differentiation and growth factors GM-CSF and Flt3L, and prior work has
shown that the NFkappaB signaling system is an important regulator. Yet given the complexity of this multi-
transcription factor, multi-regulator signaling system, its roles in subtype-differentiation, proliferation, and in
disease remain poorly understood.
In the proposed project we will examine the role of NFkappaB control in coordinating differentiation programs of
dendritic cells into two developmental pathways. Based on our preliminary results we propose the
overarching hypothesis that proper stepwise assembly of the NFkappaB signaling system during DC
differentiation pathways is critical for phasing proliferation and maturation; while classical IkappaBalpha, -Beta, -epsilon mediate
transient NFkappaB inflammatory responses, the recently described IkappaBsome plays a critical buffering and
coordinating role in DC differentiation. Misregulation of the IkappaBsome leads to severe but surprisingly different
phenotypes in the two DC developmental pathways.
We will combine an experimentally validated mathematical model of NFkappaB signaling during dendritic cell
differentiation and function, with quantitative biochemical, flow cytometric, and live cell fluorescence
microscopy, interferometry and lineage tracking studies involving knockin reporter mice, and a number of novel
genetic mouse strains to uncover the molecular basis of NFkappaB misregulation associated with myeloprolferative
disorders (MPD) and Langerhans Cell Histiocytosis (LCH). We will apply these insights about the IkappaBsome
regulation to examine patient samples and the efficacy and risks of potential drug targets.

## Key facts

- **NIH application ID:** 10375381
- **Project number:** 5R01AI127867-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Alexander Hoffmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $415,163
- **Award type:** 5
- **Project period:** 2018-04-03 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375381

## Citation

> US National Institutes of Health, RePORTER application 10375381, The NFkB System in Dendritic Cells (5R01AI127867-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375381. Licensed CC0.

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