# Assessing the effects of peripheral immune activation on the NVU following TBI using a vascularized and perfused human blood/BBB model

> **NIH NIH R33** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $497,625

## Abstract

PROJECT SUMMARY
Traumatic brain injury (TBI) is one of the leading causes of death and disability and represents the most well-
established environmental risk factor for cognitive impairment, progression to clinical Alzheimer’s disease (AD)
and AD related dementia (ADRD). Following injury, brain blood vessels undergo many degenerative changes
ranging from, loss of pericytes (PC), remodeling of the vascular basement membrane (vBM), loss of blood-brain
barrier (BBB) integrity and impaired angiogenesis, which ultimately cause neuronal damage, cognitive decline
and ADRD/AD. BBB disruption in the human hippocampus predicts cognitive impairment in patients. In addition,
the acute inflammatory phase following TBI correlates with post-TBI ADRD/AD trajectories, supporting the idea
that the initial innate immune response, may influence the later adaptive immune response, resulting in
unresolved inflammatory responses, and the risk of post-TBI cognitive impairments and ADRD/AD - progressive
disorders that worsens over time. Yet, the molecular mechanisms that predispose TBI survivors to an increased
risk of ADRD/AD are unknown and consequently there are no treatments. Our parent grant (R33HL159949),
which focuses on understanding the effects of the blood components on NVU function following TBI, compared
to control, is importantly related to the development of ADRD/AD. A major impediment to the development of
therapeutic approaches to neurological disorders has been the lack of human in vitro NVU models that mirror
the spatial organization and molecular characteristics of NVU cells in the human brain. To address this challenge,
during the R61 phase, we established a 3D human blood-BBB interface microfluidic model, which allows for the
integration of defined iPSC derived cell types forming the functional NVU, and sera from patient or controls. The
focus of the R33 phase is to examine the effect of blood components (sera and immune cells) from donors
with/without TBI on BBB/NVU function. This timely Supplement proposal requires research beyond our funded
grant to test this hypothesis through two new aims in line with the original aims from our R33. The overall goal
of this Supplement is to better understand how changes within the acute and chronic peripheral immune
response following TBI, may influence BBB/NVU function over time, and predict progression of post-TBI
associated cognitive impairments and ADRD/AD. In this proposal, we outline a plan to examine the effect of sera
from Veterans (LIMBIC-CENC cohort) with chronic TBI whom develop post-TBI associated ADRD/AD, or do not,
in the BBB/NVU. Specifically, we will examine the influence on BBB cell biology (structural and functional BBB
properties) and NVU function (cell-cell interactions and -communication and functionality). We will use state-of-
the-art single cell kinetic imaging (KIC), transcriptomics, and functional approaches to address these questions.
The proposed work may facilitate discovery of pote...

## Key facts

- **NIH application ID:** 10940105
- **Project number:** 3R33HL159949-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Dritan Agalliu
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $497,625
- **Award type:** 3
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940105

## Citation

> US National Institutes of Health, RePORTER application 10940105, Assessing the effects of peripheral immune activation on the NVU following TBI using a vascularized and perfused human blood/BBB model (3R33HL159949-04S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10940105. Licensed CC0.

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