# Role of Microglial Hur in promoting neuroinflammation and ALS disease progression

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that leads to progressive
weakness and death. There is no effective treatment, leaving the patient (and family) burdened with an
overwhelming emotional, physical and monetary fallout as the disease progresses. The physician can provide
some symptomatic relief, but there is a deep sense of frustration in not being able to treat the disease,
underscoring a strong need to identify new treatments. Veterans of foreign wars have a significantly higher
incidence of ALS than the civilian population, and thus investigations into disease mechanisms and novel
therapeutic pathways, such as the one proposed here, are of direct relevance to the VA mission.The ever
growing list of genes linked to ALS implicates a wide range of molecular pathways in disease initiation.
Neuroinflammation, however, is a common downstream element in ALS that, independent of the disease
initiating factor, can modulate disease progression. Microglia are a major component of neuroinflammation and
play dual roles in ALS: on the one hand delaying clinical onset and progression early in the disease and on the
other hand accelerating disease progression in later stages. The diversity of these roles reflects the broad and
dynamic molecular repertoire of the microglial cell. Understanding the determinants of this repertoire is critical
for opening up new therapeutic approaches. In our preliminary data and recent publication, we have identified
the RNA binding protein HuR as a major promoter of inflammatory cytokine and chemokine production in
microglia and a suppressor of anti-inflammatory cytokines. Through the regulation of downstream targets, we
found that HuR drives many cellular properties of microglial activation including migration, invasion and the
chemoattraction of other immune cells. This background forms the basis of our hypothesis that HuR plays a
pivotal role in ALS by promoting the molecular underpinnings of pro-inflammatory activation in microglia and
suppressing the molecular program that promotes an anti-inflammatory, disease delaying phenotype. We
propose three specific aims to address this hypothesis: 1) determine the molecular mechanism of pro-
inflammatory cytokine attenuation and anti-inflammatory cytokine augmentation in wild-type and ALS-
associated microglia after HuR knockout, 2) characterize the impact of HuR knockout on wild-type and ALS-
associated microglial activation, migration/invasion in response to inflammatory signals and on chemoattraction
of other immune cells, and 3) characterize the impact of HuR knockout in microglia on ALS onset and
progression in the mutant SOD1 mouse. We recently developed a mouse model in which HuR is genetically
deleted from microglia and this will greatly facilitate the completion of these aims. The long term objective of
this proposal is to characterize the role of post-transcriptional gene regulation in governing the molecular and
cellular phenoty...

## Key facts

- **NIH application ID:** 9859193
- **Project number:** 5I01BX004419-02
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** PETER H KING
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859193

## Citation

> US National Institutes of Health, RePORTER application 9859193, Role of Microglial Hur in promoting neuroinflammation and ALS disease progression (5I01BX004419-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859193. Licensed CC0.

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