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For people outside the world of cell biology, the term blood-brain barrier tends to conjure images of a large singular membrane surrounding our brains, as if it were a stone wall protecting a medieval castle. But rather than encasing the brain, the blood-brain barrier exists within it, winding its way through the brain as a tightly packed network of blood vessel cells and tissues. Moreover, since our brains, just like any other organ, must be nourished by nutrient-rich blood, this barrier can’t only keep harmful things out. The secret to the BBB’s effectiveness is its semipermeability: It works its magic by selectively allowing vital nutrients, like oxygen and glucose, to reach our brains, turning away pathogens and toxins, and funneling other things, like waste, away. 

It’s a complex system that consists of many types of cells and processes, and it’s one that still presents many mysteries for scientists, says Elena Zhang, an MD and associate professor of neurobiology. One of the most exciting research frontiers is the relationship between the BBB and an arguably even more enigmatic cerebral feature called the neurovascular unit. The NVU, like the BBB, isn’t so much a discrete part of the brain as it is a system. A relatively new concept in neuroscience, the NVU generally describes a set of neurons and blood vessel cells that work together to support the metabolic needs of the brain at vital locales where substances are moved to or from the bloodstream and surrounding cerebral  tissue. As such, it’s not surprising that the NVU is thought to play a critical role in regulating the BBB. But Zhang says it actually wasn’t that long ago that scientists thought neurons really didn’t play an important role in the BBB. “Now we understand that the NVU is this complex team of cells that orchestrate the two-way traffic across the blood-brain barrier,” she explains. “And it’s not just one process. Sometimes molecules might diffuse across the barrier. Other times they might need transport. So it takes an incredible amount of cooperation between all the cells on the team.”

Neurobiologists are still working out the particulars of all the mechanisms that are vital to the NVU’s functioning, and Zhang is hoping a new $465,000 National Institutes of Health-funded project with Assistant Professor of Biology Jie Fan could help scientists untangle a few of the key mysteries, particularly how the NVU helps regulate the BBB. To accomplish this, they’ll be looking at an instance when the BBB is particularly vulnerable — namely, after a head trauma. Zhang, who’s done previous work on pediatric head injuries, says even small traumas, including quick accelerations and decelerations of the head, can damage cerebral tissue, including the NVU. And her previous research indicates that this damage does indeed threaten the integrity of the BBB, though what exactly is going haywire within the NVU after injury isn’t yet clear.

For Zhang and Fan to understand what might be going on, they have to start with some pretty involved science. Direct observation in the brain at this neurovascular level after an injury is simply not possible — you can’t just cut people’s heads open and look at what’s inside. Nor is that even possible in the mice models they’re using for this stage of their research. To peer this deeply into the brain, Zhang and Fan will actually first have to get tissue out of it — extracting samples from mice that have sustained head trauma. They then have to meticulously separate the different types of cells in the sample, isolating all the most important cell types of the NVU and culturing each one so they have enough to study. Then it’s time to start looking for answers. Zhang will be using a variety of techniques to look for ways trauma may be expressed at the cellular level, including testing for genetic markers. “A trauma can cause our cells to turn on or off different genes as they try to respond to the injury, and they can even change into different cell subtypes,” she explains. “Some ‘good’ cells might turn into ‘bad’ ones, and it’s even possible for the same cell to sometimes be ‘good’ and sometimes be ‘bad.’ So we can look for these genetic markers to see if, for example, certain proteins are being made or a certain cell type has become overactive.”

Another thing Zhang and Fan are interested in is a phenomenon called cell chirality. This refers to the slight helical twist that’s characteristic of the endothelial cells that make up the walls of blood vessels. This twist allows the cells to lock together very tightly, and Fan’s earlier work on cancer metastasis has found that a loss of chirality can lead to leaky vessels. Given the crucial role endothelial cells play in the NVU,  Zhang and Fan want to know whether chirality may be playing a role in the malfunctioning of the BBB after injury. 

Since the NVU is really a team of cells, Fan and Zhang will also be trying to observe changes in how the cells work together post-trauma. To do this, they’ll culture the different cell types and then reintroduce them to each other in a Petri dish to see how well they play together. “This is probably the most challenging part of the project, because when we isolate the cells and put them together and observe their interactions, whether their interactions are true, or represent how they would function in the body, is difficult to say for sure,” Fan says. “But this is how you have to start. You look for interactions that seem interesting and go from there. Unfortunately, you can’t put everything back in the brain, because everything is mixed together and you can’t see it.”

If successful, this research could be a significant contribution to scientists' quest to more adequately describe the various processes of the NVU. But in many ways, Zhang and Fan say it’s just the starting point. The ultimate goal is to develop therapeutics that could help the brain regain healthy function after injury. And to do that, scientists first must have a thorough understanding of how the NVU works and what processes are malfunctioning post-trauma. Zhang, whose background also includes nanomedicine development, says the best therapeutics will likely be ones that target restoration of specific processes — and can get past the blood-brain barrier, which is what makes nanomedicine a promising option. One unfortunate side effect of the BBB’s effectiveness in keeping pathogens and toxins out of our brains is that it also keeps most medicines out. “There are many pharmaceutical companies trying to develop drugs for the central nervous system, but many of the clinical trials haven’t been very successful — primarily because of this challenge of the blood-brain barrier,” Zhang explains. “We’re seeing very little bioavailability or uptake in the areas we want, so they’re not performing as they should. Nanomedicines may have more success not only crossing the blood-brain barrier, but, if you design the medicine correctly, they can repair the specific cells and tissues. But before we reach this amazing future, we need to figure out what’s really going on. Only then can we target the specific receptors, transporters, cells or cell-cell interactions that our body needs to heal itself.”

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Story by Lou Blouin