# Molecular genetic analyses of transcriptional dysregulation in Alzheimers disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $726,908

## Abstract

Project Summary/Abstract
Recently, multiple human genetic studies have identified the critical role of the immune system in the
pathogenesis of Alzheimer’s disease (AD). For example, microglia phagocytose amyloid beta (Abeta) and
regulate brain immune function by secreting cytokines and chemokines. Because previous studies have
suggested both protective and detrimental effects of microglial activity in AD, how microglial AD risk genes, such
as PU.1, affect microglial function still remains unclear. Therefore, investigating the role of AD genetic risk factors
in microglia will provide critical insight into the pathobiology of the disease, potentially revealing key regulators
of underlying disease mechanisms and novel therapeutic targets. An AD genetic risk factor, PU.1, is a critical
transcription factor selectively expressed in microglia in the brain. We hypothesize that PU.1 affects several
transcription pathways, Abeta metabolism and other AD-related pathologies by regulating their immune function.
To test this hypothesis, we will apply several innovative technologies, including single-cell RNA-sequencing,
quantitative proteomics, super-resolution microscopy, human-induced pluripotent stem cell-derived microglia
and neurons, multi-electrode arrays, electrophysiology, and the simultaneous Positron Emission Tomography-
Magnetic Resonance Imaging, in collaboration of multiple collaborators with extensive experience in these
methods. In aim 1, we will determine how downregulating PU.1 affects microglial and neuronal phenotypes and
perform unbiased transcriptomic and proteomic analyses to identify key downstream regulators. In aim 2, we will
investigate the functional interaction between microglia and neurons using human induced pluripotent stem cells
after regulating PU.1 expression. In aim 3, we will terminate how microglial PU.1 affects AD phenotypes when it
is regulated before and after the onset of amyloid pathology.

## Key facts

- **NIH application ID:** 10467106
- **Project number:** 1R01AG077829-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jungsu Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $726,908
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467106

## Citation

> US National Institutes of Health, RePORTER application 10467106, Molecular genetic analyses of transcriptional dysregulation in Alzheimers disease (1R01AG077829-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467106. Licensed CC0.

---

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