# Decoding Alzheimer's disease-related enhancers in microglia

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $39,517

## Abstract

Project Summary/Abstract
 Late-onset Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by
progressive loss of memory and other cognitive functions. While the pathology and clinical course of
AD is well-documented, there are presently no effective disease-modifying therapies or cures in
existence. With the incidence of AD expected to climb over the next half century, it is important to further
investigate the molecular and cellular mechanisms underlying AD. Genome-wide association studies
have identified genetic variants that are highly associated with AD, but their contributions to AD have
not been completely elucidated. Bridging Integrator 1 (BIN1) is one of these genes; although it is known
to play a role in cellular processes such as endocytosis and membrane trafficking, little is known about
how the gene is regulated and how it impacts AD pathogenesis. Further, BIN1 is known to be expressed
in neurons, oligodendrocytes, and microglia, yet few studies have focused on microglia-specific BIN1
expression in AD. Our lab has identified a DNA regulatory region, called an enhancer, in microglia
upstream of the BIN1 promoter that also contains an important AD risk variant. The central hypothesis
of this proposal is that the expression of BIN1 is regulated by the putative BIN1-associated enhancer
and that an AD variant within the enhancer modulates gene expression.
 This proposal describes an in vitro system that will systematically screen the putative microglial
BIN1 enhancer for functional elements using CRISPR-mediated genome editing strategies. These
studies will provide an idea of which non-coding regions of the genome are important for controlling
BIN1 expression in microglia. Finally, the effect of an AD risk variant on gene expression will be studied
using a novel in vivo enhancer-reporter assay. Understanding gene regulatory mechanisms in microglia
is an important step towards fully defining the cellular and molecular mechanisms underlying AD risk.
This proposal addresses a growing need to approach diseases from the perspective of genomics and
gene regulation and will provide proof of concept for a general approach linking genetic variants with
functional consequences in a cell- and disease- specific context.
 The proposed research will take place in the Glass Laboratory at UCSD. The lab has expertise
in tissue-resident macrophage gene regulation and is composed of a diverse group of scientists whose
specialties ranges from bioinformatics to cell biology. Through graduate coursework, mentorship, and
hands-on learning, Bethany will gain experience in approaching large datasets from a quantitative
perspective and will learn cutting-edge wet lab techniques; these skills will be valuable for the
completion of the proposed research and for Bethany’s future career as a physician-scientist.

## Key facts

- **NIH application ID:** 9973119
- **Project number:** 5F30AG062159-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Bethany Rose Fixsen
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,517
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973119

## Citation

> US National Institutes of Health, RePORTER application 9973119, Decoding Alzheimer's disease-related enhancers in microglia (5F30AG062159-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973119. Licensed CC0.

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