# Elucidating SHIP1 in microglia in health and disease

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $33,743

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects more than 5 million people in
the United States. The underlying cause of neuronal synaptic loss and neurodegeneration in AD is incompletely
understood. Recent studies have directed research efforts towards elucidating the role of microglia and
neuroinflammation in the progression of AD. Phosphatidylinositol-3,4,5,-triphosphate 5-phosphatase 1
(INPP5D/SHIP1) is a phosphatase that is a negative regulator of PI3K/Akt signaling, and this enzyme has a
known role in suppressing macrophage activation in the peripheral immune system. The expression of SHIP1 is
restricted to cells of the hematopoietic lineage, which includes microglia. rs35349669, an INPP5D-associated
SNP, has been implicated in an increased risk for late-onset or sporadic Alzheimer’s disease (LOAD) in a large
GWAS meta-analysis. Furthermore, the products of the enzymatic activity of SHIP1 have been linked to AD-
relevant signaling cascades. The goal of this proposal is to understand the function of SHIP1 in microglia and to
investigate whether SHIP1 plays the same immune modulatory role it does in microglia that it does in peripheral
macrophages.
The studies outlined in Aim 1 will test the hypothesis that SHIP1 is a negative regulator of microglia immune
activation by examining both patient-derived induced pluripotent stem cell (iPSC) derived microglia-like cells
(iMGLs) as well as microglia in vivo in microglia-specific SHIP1-deficient mouse models. The studies outlined in
Aim 2 will work to understand the functional consequence of SHIP1 activity and signaling in the microglia on
neurons, specifically through quantification of neuronal synapse numbers by culturing iMGLs with iPSC-derived
neurons (iN) in an in vitro co-culture system as well as in microglia-specific SHIP1-deficient AD mouse models.
Ultimately, understanding the role that SHIP1 plays in microglia immune activation and activity will allow for a
greater understanding of AD pathobiology and to better define the molecular processes underlying innate
microglial biology.

## Key facts

- **NIH application ID:** 10057209
- **Project number:** 5F31AG063398-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Vicky Chou
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,743
- **Award type:** 5
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057209

## Citation

> US National Institutes of Health, RePORTER application 10057209, Elucidating SHIP1 in microglia in health and disease (5F31AG063398-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10057209. Licensed CC0.

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