# molecular mechanisms of the blood brain barrier function and regulation

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2020 · $1,009,297

## Abstract

Project Summary/Abstract:
The central nervous system (CNS) requires a tightly controlled environment free of various toxins and
pathogens to provide the proper chemical composition for synaptic transmission. This environment is
maintained by the `blood brain barrier' (BBB), which is composed of highly specialized blood vessels whose
endothelial cells display specialized tight junctions and unusually low rates of transcellular vesicular transport
(transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals
the CNS and controls substance influx and efflux. While BBB breakdown has recently been associated to
initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery
to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hampered
our ability to manipulate the BBB in disease. Our recent discoveries changed our understanding of what
makes the BBB impermeable. The BBB is formed by a single layer of endothelial cells that lines the walls of
the brain's blood vessels. Historically, the restrictive feature of BBB has been attributed to the specialized tight
junctions between adjacent endothelial cells. However, substances can also cross the endothelial layer by
transcytosis, when material enters endocytic vesicles that are trafficked across the cell. We discovered that
transcytosis is actively inhibited in brain endothelial cells to ensure BBB integrity. Our findings suggest that
molecular pathways inhibiting transcytosis could be targeted to open the BBB for CNS therapeutics.We have
also identified over 200 BBB candidate genes that are enriched in CNS endothelial cells compared to periphery
endothelial cells. I propose to launch major new efforts leading to a major expansion in the scope of our work
in the field of BBB. I will take the next eight years to bring my lab to the next level to (1) identify the full list of
key BBB regulators in CNS endothelial cells, (2) understand what signals from non-endothelial cells maintain
and regulate BBB permeability, and (3) determine how BBB permeability dynamically changes during different
physiological and pathological conditions. We will also begin to work on translating findings from these studies
to therapies. We will use a combination of mouse genetics, imaging, molecular, cell biology, and biochemical
approaches. The experiments described here represent a major expansion in the scope of our work. Achieving
the goals outlined here could have a major impact on neurology, enabling clinicians to open the BBB for
transient delivery of drugs to the CNS, and conversely to close the BBB to slow the progression of
neurodegenerative diseases. Given the transcriptome screens we have recently performed, the model systems
we have devised, and the imaging tools we have recently developed, my lab is in a unique position to reveal
the molecular and cellular mechanisms of the B...

## Key facts

- **NIH application ID:** 9985356
- **Project number:** 1R35NS116820-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** CHENGHUA GU
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,009,297
- **Award type:** 1
- **Project period:** 2020-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985356

## Citation

> US National Institutes of Health, RePORTER application 9985356, molecular mechanisms of the blood brain barrier function and regulation (1R35NS116820-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985356. Licensed CC0.

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