# Mechanisms controlling human microglia gene expression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $471,589

## Abstract

Abstract
Microglia are tissue macrophages that reside in the central nervous system (CNS) and perform unique and
critical auxiliary functions important to CNS development, homeostasis, immunity and repair. These roles, along
with the progressive appreciation that microglia can contribute to neurological disease processes, provides a
compelling case to more clearly understand the mechanisms that regulate their development and functions.
Major unanswered questions include determining the combination of signals within the brain that trigger the
differentiation of erythromyeloid progenitor (EMP) cells to become mature microglia and how alterations in these
signals specify distinct microglia phenotypes in health and disease. Studies performed under the support of this
grant for the past four years provide the foundations for addressing these questions. Four Specific Aims are
proposed. Specific Aim 1 is to define expression and chromatin Quantitative Trait Loci and collaborative
transcription factors in human microglia. These studies will generate a valuable resource for the neuroscience
community and inform studies in Aims 2, 3 and 4. Specific Aim 2 is to define cis regulatory elements that mediate
brain environment-dependent regulation of microglia gene expression, focusing on the microglia-specific lineage
determining factor SALL1. Importantly, our experimental plan will exploit the recent ability to achieve an in vivo
human microglia phenotype within the mouse brain as the context for analysis of the function of environment-
dependent enhancers. Specific Aim 3 is to test the hypothesis that brain environment-dependent genes can be
activated in iPSC-derived microglia in vitro by conditional expression of environment-dependent transcription
factors. Forced expression of these factors in human iPSC-derived microglia in vitro will provide insights into
their molecular functions and may enable development of improved in vitro microglia model systems. Specific
Aim 4 is to perform in vivo ASO-mediated loss of function experiments to identify transcriptional mediators of
brain environmental factors. This aim is based on advances in anti-sense oligonucleotide (ASO) chemistry that
now make it possible to use ASOs to significantly alter gene expression in microglia and other cell types of the
brain in vivo. In concert, the proposed studies are intended to qualitatively advance understanding of
mechanisms that establish the brain environment dependent program of human microglia gene expression.

## Key facts

- **NIH application ID:** 10495183
- **Project number:** 5R01NS096170-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christopher K Glass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,589
- **Award type:** 5
- **Project period:** 2016-05-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495183

## Citation

> US National Institutes of Health, RePORTER application 10495183, Mechanisms controlling human microglia gene expression (5R01NS096170-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10495183. Licensed CC0.

---

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