# Understanding the role of senescence on post-operative neuroinflammation

> **NIH NIH RF1** · DUKE UNIVERSITY · 2022 · $2,268,715

## Abstract

Abstract
Peripheral tissue injury, which arises due to surgical trauma, can negatively impact brain function, particularly in
older and/or
frail patients that may already suffer from neurodegeneration and Alzheimer’s disease (AD). The
blood-brain barrier (BBB) represents a key interface between the periphery and the brain with important roles in
regulating neuroimmune interactions. Dysfunction of the BBB has been reported in many neurologic conditions,
including AD and Alzheimer’s Disease Related Dementias (ADRD). BBB dysfunction during normal aging can
also contribute to neuroinflammation and cognitive loss via altered transcellular permeability, trafficking of blood-
derived factors in the brain parenchyma. BBB dysfunction and neuroinflammation are growing significant interest
in postoperative complications such as delirium. Indeed, delirium is a form of ADRD that is associated with worse
outcomes both in patients with and without neurodegeneration, and is especially common following major
surgery such as orthopedic procedures. In this research, we will address why the aging brain is more susceptible
to postoperative delirium and neuroinflammation by using a clinically relevant orthopedic fracture model in mice
that displays various cardinal features of BBB impairment, glial dysfunction, and cellular senescence. Our central
hypothesis is that senescent cell burden in aged individuals exacerbates systemic inflammation, hastens BBB
breaching, and promotes neuroinflammation leading to delirium. We will test this hypothesis by combining a
transgenic mouse model and pharmacological drug-mediated elimination of senescent cells. The latter will also
lead to the validation of a clinically applicable therapeutic formulation/regimen to treat post-operative
neuroinflammation and delirium with drugs (senolytics) currently tested in humans for other disorders, including
AD. We have 3 objectives: 1) determine the role of senescent cells on systemic inflammation, BBB breaching,
and neuroinflammation following surgical trauma, 2) examine the efficacy of senolytic drug, D/Q-mediated
senescent cell clearance in preventing neuroinflammation, and 3) determine the reciprocal interactions between
the blood-borne factors and the BBB using a microphysiological system. Together the studies will provide new
insights into the effects of peripheral surgical trauma on the blood-brain interface, neuroinflammation, and
cognitive impairments such as delirium. This is a highly significant step toward identifying pharmacologic targets
to prevent delirium and improve outcomes after surgery in elderly patients.

## Key facts

- **NIH application ID:** 10520248
- **Project number:** 1RF1AG076203-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Niccolo Terrando
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,268,715
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520248

## Citation

> US National Institutes of Health, RePORTER application 10520248, Understanding the role of senescence on post-operative neuroinflammation (1RF1AG076203-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10520248. Licensed CC0.

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