# LRP1 as a novel regulator of CXCR4 in adult neural stem cells and post-stroke response

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $76,375

## Abstract

Project Summary/Abstract
The good news is that increasingly, patients who experience an ischemic stroke survive. Unfortunately, survivors
are rarely unscathed — stroke is the leading cause of long-term disability in the U.S. Interventions are limited in
part due to a lack of insight into secondary processes post-stroke. Neural stem cells (NSCs) have demonstrated
therapeutic benefit in stroke recovery. But key questions remain that if answered, could enhance clinical use.
NSCs normally migrate to the lesion, secrete pro-reparative factors, differentiate, and reduce secondary damage.
Central to these benefits is the ability of NSCs to send and respond to specific environmental cues. Our data
show NSC function is influenced by low-density lipoprotein receptor-related protein (LRP1), a multifunctional
receptor that modulates cell signaling via multiple mechanisms. Despite an expansive role in signal modulation,
the importance of LRP1 in NSC biology is virtually unstudied. We knocked-out LRP1 in adult NSCs and subjected
mice to middle-cerebral artery occlusion. We found LRP1-KO in NSCs ablated migration to ischemic lesions.
We also discovered that functional impairment and lesion size were reduced. This observation is somewhat
paradoxical-physical localization of NSCs to lesions is often considered important to neuroprotective efficacy.
We also found that LRP1-KO ablates expression of CXCR4, a chemokine receptor which is essential for
migration to ischemic lesions. Thus, we seek to better understand how impaired LRP1 expression in NSCs is
neuroprotective, and similarly to understand the mechanisms underlying LRP1 regulation of CXCR4. Our overall
hypothesis is that LRP1 promotes NSC migration toward ischemic lesions through CXCR4 regulation,
yet also limits the endogenous NSC-neuroprotective response. Our data suggest that LRP1 is a major driver
of NSC response to signals. This proposal investigates LRP1, CXCR4, and NSC function in stroke using surgical
models, in vivo, and in vitro approaches. We utilize a Nestin-CreERt2 mouse model to direct knock-out of LRP1
and/or CXCR4 in NSCs and to track these cells with expression of red fluorescent protein. Aim 1 tests the
hypothesis that NSC-mediated neuroprotection is due to loss of LRP1, which promotes recovery
independent of effects on CXCR4 by measuring post-stroke outcomes after rescuing expression of CXCR4 in
mice with LRP1-KO in NSCs, or ablating LRP1 in mice with CXCR4-KO in NSCs. Aim 2 tests the hypothesis
that loss of LRP1 (or CXCR4) is neuroprotective by enhancing post-stroke NSC neuroprotective
response by interrogating the effect on NSC post-stroke response and survival, both in vivo and in vitro. Aim 3
tests the mechanism by which LRP1 regulates CXCR4 expression by rescuing LRP1 with domain-specific
constructs and elucidating the effect on transcription, signaling, trafficking, and degradation of CXCR4. Data
from these studies will define the value of NSC-LRP1 as a therapeutic target, identify d...

## Key facts

- **NIH application ID:** 11057547
- **Project number:** 3R01NS132778-02S1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Naomi Ledene Sayre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,375
- **Award type:** 3
- **Project period:** 2023-08-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11057547

## Citation

> US National Institutes of Health, RePORTER application 11057547, LRP1 as a novel regulator of CXCR4 in adult neural stem cells and post-stroke response (3R01NS132778-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11057547. Licensed CC0.

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