# A Vascularized Micro-Organ platform for the study of Brain-BBB-Blood interaction

> **NIH NIH R33** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $638,729

## Abstract

PROJECT SUMMARY
For too long, studies of the Blood-Brain Barrier (BBB) have ignored the blood component of this interface,
focusing almost exclusively on the cells of the Neurovascular Unit (NVU). The goal of the FOA to which we are
responding aims to change this:
 “The intent of this FOA is to stimulate the development of a new field of blood-based science by re-defining
 the neurovascular unit as a component of the blood-brain interface. This will facilitate development of human-
 based neurovascular-blood models to identify targets for diagnostics and regulation of the blood-brain
interface…”
The NVU is comprised of endothelial cells (EC), pericytes and astrocytes, and a complex basement membrane,
which work together to severely limit the free movement of molecules from the blood into the brain parenchyma.
In response to local signals during development BBB EC develop tight junctions and have very low rates of
transcytosis. The side-effect of this is that access of potentially therapeutic drugs into the brain is also
compromised. In this proposal we will build on our well-established human Vascularized Micro-Organ (VMO)
platform to create a novel blood-brain interface model, the VMO-B. In this model a network of human
microvessels anastomoses to microfluidic channels representing an artery and a vein and are induced to a BBB
phenotype by Wnt signaling. The vessels are invested by pericytes and contacted by astrocyte foot-processes.
Importantly, we will run a blood substitute – VMOBlood – through the vessels that will mimic the composition of
blood, including protein and lipid content. We will then use the VMO-B to investigate the process of BBB
breakdown in the pathogenesis of Huntington’s disease. We already have preliminary data suggesting that
expression of mutant HTT protein in EC causes BBB deficits. We will investigate crosstalk between blood and
the cells of the NVU, and how expression of mHTT in each cell type affects cell-cell communication and barrier
function. In the R61 phase we will pursue three aims: Aim 1 Develop a stable MPS BBB model with perfused
microvasculature; Aim 2 Incorporate flow of blood into BBB microfluidic model; and, Aim 3 Characterize key
transporters at the blood-brain interface. In the R33 phase we will use this platform to examine the role of the
blood-brain interface in the pathology of HD through an additional two aims: Aim 4 Test the hypothesis that
expression of mHTT in EC disrupts transport across the BBB leading to changes in the neural micro-environment;
and, Aim 5 Test the hypothesis that expression of mHTT disrupts multiple cell-to-cell interactions at the blood-
brain interface. Completion of this project will not only shed light on the neuropathology of Huntington’s
disease, but will also yield a platform ideally suited to drug development and investigating the role of the blood-
brain interface in numerous neurological diseases including Alzheimer’s disease, Multiple Sclerosis, Parkinson’s
disease,...

## Key facts

- **NIH application ID:** 10701037
- **Project number:** 5R33HL154307-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** CHRISTOPHER C. W. HUGHES
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $638,729
- **Award type:** 5
- **Project period:** 2020-09-03 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701037

## Citation

> US National Institutes of Health, RePORTER application 10701037, A Vascularized Micro-Organ platform for the study of Brain-BBB-Blood interaction (5R33HL154307-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10701037. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*