# Creation of new tools to study human microglia using blood cells

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2021 · $58,274

## Abstract

Contact PD/PI: BENNETT, FREDERICK
PROJECT SUMMARY/ABSTRACT
Microglia, the brain's resident immune cells, are essential for normal brain development and function, and likely
involved in mental illnesses such as depression and schizophrenia. Because it is nearly impossible to obtain
suitable human brain specimens, we are severely restricted from studying microglial function in these
diseases, especially in vivo. This Mentored Career Development Award, by a clinician-scientist in the
Departments of Psychiatry and Neurobiology at Stanford University, mentored by Dr. Ben Barres, will make the
study of human microglia in mental illness a reality through related basic and translational research goals. The
basic research goal is to advance our understanding of microglial biology by comparing the transcriptomes of
microglia and blood-derived “Microglia Like Cells” (MLCs) that enter the brain during disease. The translational
goal is to use these results to generate human microglia from blood cells, allowing study of microglia without
human brain tissue. This proposal outlines a 5 year mentored career development plan that harnesses the
abundant educational and scientific resources at Stanford to accomplish the research aims described below
while providing the candidate with needed training to function as an independent investigator.
Preliminary data show that when mice lacking microglia due to knock-out of the CSF1 receptor (CSF1R) are
transplanted with wild type (WT) bone marrow (BM), donor-derived cells fill the brain in a near-identical pattern
to WT microglia, and express nearly all specific markers of microglial fate. These engrafted MLCs can be
purified based on expression of Tmem119, a highly specific mouse and human microglial marker. RNAseq
data shows that MLCs are highly similar to WT microglia. The proposed research will expand on these
intriguing findings to better understand differences between MLCs and microglia, and create a reliable system
for studying bone marrow-derived MLCs in vivo. Aim 1 will determine how closely MLCs resemble WT
microglia, and in what ways they are different. Aim 2 will identify the specific hematopoietic cell types capable
of generating MLCs. Aim 3 will translate these findings for use with human blood cells, by generating RNAseq
profiles for highly pure resting human microglia, and comparing them to MLCs generated by transplantation of
human BM into immunodeficient humanized mice. This work will advance our understanding of core
differences between microglia and MLCs, identify the transcriptomic signature of pure human microglia, and
create a tractable system to study microglia using patient-derived hematopoietic cells, while fostering an
independent research career centered around the role of microglia in mental health.
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Project Summary/Abstract

## Key facts

- **NIH application ID:** 10378989
- **Project number:** 3K08MH112120-05S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Frederick Bennett
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $58,274
- **Award type:** 3
- **Project period:** 2019-07-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378989

## Citation

> US National Institutes of Health, RePORTER application 10378989, Creation of new tools to study human microglia using blood cells (3K08MH112120-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378989. Licensed CC0.

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