# Dynamic Circadian Regulation of the Blood-Brain Interface in a Human Brain-mimicking Microfluid Chip

> **NIH NIH R61** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $836,237

## Abstract

Cerebral microbleeds (CMBs) and microhemorrhages (CMHs) result from blood leakage across the blood-
brain interface (BBI). Subsequent millimeter-sized blood clots lead to inflammation, cellular injury, and neuro-
degeneration. Such CMBs are associated with deterioration of BBI integrity with aging, disease, traumatic brain
injury, and the sequelae of strokes, which impact >795,000 people in the United States every year. Notably,
CMBs and hemorrhagic/ischemic stroke occurrence is not random, but rather clusters in early day or evening.
Understanding of the circadian dynamics of the BBI with respect to vulnerability to blood leakage is limited. It
has been difficult to study in vivo or via on-chip models and there is no drug treatment. In addressing this gap,
this proposal responds to FOA RFA-HL-20-021. The purpose of this FOA is to support high risk/high reward
research on the blood component of the Blood-Brain Barrier and the associated Interface to facilitate the
development of a more complete neurovascular-blood model for translational applications with direct relevance
to humans. It is an R61/R33 Exploratory /Developmental Phased Award. Because knowledge of the circadian
dynamics in BBI vulnerability to blood leakage is limited, we aim to create a new biomimetic brain transport
model with mimicry of the coagulation system and circadian rhythm. We will develop an innovative microfluidic
platform to examine interactions of coagulation factors and circadian oscillations of both 1) the blood/vascular
components and 2) dynamic vascular pressure across the BBI over the circadian cycle. We propose to
reproduce circadian dynamics of the BBI by culturing human endothelial cells containing a clock-gene reporter
on the ‘vascular’ side with polarized astrocytes, neurons, and microglia in the ‘brain’ compartment. This project
assembles the expertise needed to facilitate the creation of enhanced platforms that more closely model the
human BBI. Contributions of team members will be: Han–Microfluidics and biotransport analysis; Kong–
engineering of BBI; Gillette–Assemble/validate a human iPSC circadian reporter-in-chip and assess rhythms
and fluxes, and consultation from Flick on blood coagulation factors and Obrietan on the circadian reporter
transgene. This grant will be separated into 2 phases: Focus in YR 1-2 (R61) will be on establishing tools and
in YR 3-5 (R33) on utilizing those tools to achieve our research goals. This will enable us to replicate dynamics
of the BBI in human brain and to probe it in the context of the oscillatory circadian cycle that drives integrative
physiology and behavior, including sleep and wakefulness. By targeting both sides of the BBI and their
intersection, we will gain insights into the emerging view that the BBI is plastic, changing with time-of-day, loss
of sleep, the stress of infection, and aging. This has significant implications for the role of the circadian clock in
blood coagulation in the brain and neurovascular f...

## Key facts

- **NIH application ID:** 10488679
- **Project number:** 5R61HL159948-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Martha U Gillette
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $836,237
- **Award type:** 5
- **Project period:** 2021-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488679

## Citation

> US National Institutes of Health, RePORTER application 10488679, Dynamic Circadian Regulation of the Blood-Brain Interface in a Human Brain-mimicking Microfluid Chip (5R61HL159948-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488679. Licensed CC0.

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