# Molecular tools to decipher communication across the blood-brain barrier

> **NIH NIH DP5** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $403,750

## Abstract

Project Summary/Abstract
The blood-brain barrier (BBB) maintains brain health by protecting the brain from the bloodstream. These
barrier properties frustrate the treatment of nearly all brain disorders, representing one of the largest
challenges in neuroscience and drug delivery. Yet, intriguingly, recent studies have discovered a variety of
surprising peripheral influences on brain function, hinting at the existence of underappreciated modes of
communication across the BBB. Indeed, while canonical BBB properties, such as paracellular tight junctions
and minimal caveolin-mediated transcytosis, have been established via a handful of standard tracers, it
remains unclear whether these tracers fully represent the BBB’s physiological interactions with and
permeability to the thousands of circulating proteins and cells it is constantly exposed to. By developing
methods to tag and track the blood plasma proteome, I recently observed an unexpected degree and diversity
of protein transport into the healthy adult brain. Thus, I hypothesize that brain health is maintained not just by
BBB impermeability—but by specific routes of blood-to-brain communication actively facilitated by the BBB.
Specifically, I propose that there are three logical routes for how peripheral information is communicated
across the healthy BBB: the direct transport of proteins into the brain; the responsive relay of proteins made by
the BBB into the brain; and the BBB-licensed migration of peripheral immune cells into the brain. By combining
proteome tagging techniques with bioorthogonal chemistries, each proposed aim explores one independent
route to systematically reveal the identities and mechanisms of the signals transmitted via the healthy BBB. I
will begin by creating a first catalog of plasma proteins that directly cross the BBB and quantifying their
permeabilities (Aim 1). I will subsequently characterize a new BBB relay function by deducing the signals the
BBB secretes into the brain in response to peripheral cues (Aim 2). Lastly, I will elucidate neuroimmune
surveillance by determining the BBB sites and molecules enabling healthy immune cell migration into the brain
(Aim 3). Together, these studies will expand our understanding of how the BBB maintains brain health and
enable new studies exploring the neurological functions of BBB-permeable proteins and cells in health, aging,
and disease. Our results will also provide a comprehensive set of functional targets to enhance drug delivery to
the brain, reveal new mechanisms to understand and blunt neuroinflammation, and generate innovative tools
to decipher intercellular communication for broad use across disciplines.

## Key facts

- **NIH application ID:** 10704542
- **Project number:** 5DP5OD033381-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew Chris Yang
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2022-09-14 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10704542

## Citation

> US National Institutes of Health, RePORTER application 10704542, Molecular tools to decipher communication across the blood-brain barrier (5DP5OD033381-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10704542. Licensed CC0.

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