# Deciphering innate immune signaling mechanisms in glial cells linking lifetime environmental exposures to neuroinflammation, protein aggregation and neurodegeneration in Parkinsons disease

> **NIH NIH R35** · COLORADO STATE UNIVERSITY · 2024 · $1,118,461

## Abstract

Project Summary
Parkinson’s disease (PD) is a debilitating movement disorder affecting the central nervous system (CNS)
and is the second most common neurodegenerative disease worldwide after Alzheimer’s disease (AD). In
addition to age and genetic background, environmental exposures are strongly associated with the
development of PD. Agents implicated as risk factors for PD include pesticides and heavy metals, as well
as infectious agents such as bacteria and viruses. The question of how cumulative environmental exposure
to these agents throughout lifespan can promote the development of PD and related disorders remains
largely unanswered. Inflammatory activation of glial cells in the brain is recognized as a critical early event
in the prodromal phase of PD. Still, the molecular signals regulating conversion to this damaging
inflammatory phenotype are only now being elucidated. This R35/RIVER application addresses the critical
question of how the neuro-immune axis responds to environmental exposures encountered across the
lifespan and how the combination of such exposures can trigger the onset of neurological disease through
phenotypic conversion of glial cells to a neurotoxic state. To develop a deeper understanding of the
molecular regulation of phenotypic changes in glial cells that underlie the progression from prodromal to
symptomatic disease, the proposed studies will employ sophisticated transgenic models and molecular tools
to address these scientific questions. The key scientific questions raised in this application coalesce around
three well defined and interrelated goals: 1) Determine how developmental exposure to environmental
neurotoxins modulates innate immune signaling in glial cells to alter the inflammatory response of the
neuro-immune axis to subsequent toxic exposures during aging, 2) Identify key molecular pathways in glial
cells altered by exposure to environmental neurotoxicants that regulate inflammatory responses of the brain
to viral infection, and 3) Elucidate molecular signatures in regional populations of glial cells corresponding
to various states of activation across the progression of neurological disease triggered by exposure to
environmental neurotoxicants and viruses. The scientific goals addressed by this R35/RIVER application
concerning multiple exposures across lifespan and risk for neurological disease will use both long-term
studies involving exposure to multiple neurotoxic and infectious agents, as well as powerful approaches
such as high-content imaging, neural network-based informatic analysis, single-cell and spatial
transcriptomics and generation of new transgenic models. The R35 mechanism is ideal for integrating these
complex resources and approaches with the personnel expertise necessary to address fundamental questions
about how environmental exposures alter innate immune responses of the brain that promote the
development of neurological disorders like PD and AD.

## Key facts

- **NIH application ID:** 10865028
- **Project number:** 5R35ES035043-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** RONALD TJALKENS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,118,461
- **Award type:** 5
- **Project period:** 2023-06-12 → 2031-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865028

## Citation

> US National Institutes of Health, RePORTER application 10865028, Deciphering innate immune signaling mechanisms in glial cells linking lifetime environmental exposures to neuroinflammation, protein aggregation and neurodegeneration in Parkinsons disease (5R35ES035043-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10865028. Licensed CC0.

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