Discover the clues behind traumatic brain injury

“Unfortunately, the molecular and cellular mechanisms of the progression of TBI injury are not,” said Sarah Stabenfeldt, ASU professor and team leader and corresponding author of the study appearing in the journal Science Advances. still have many aspects and have not been fully elucidated. “Thus, this complexity affects the development of diagnostic and therapeutic options for TBI; the goal of our study was to address current limitations.”

Their research approach was to perform a “biologically cyclical” search to reveal several key molecular markers, known as biomarkers, that were identified shortly after the traumatic event (the stage of the traumatic event). acute phase), and also the long-term consequences (chronic phase) of TBI.

Treatment of traumatic brain injury

To overcome these limitations, ASU scientists, led by Sarah Stabenfeldt, used a mouse model for their study to begin investigating the root cause of TBI by identifying biomarkers — Unique molecular fingerprints found with a certain injury or disease.


“The neurological injury research community is a well-established field that has developed and characterized preclinical animal models to better understand TBI pathology and evaluate the efficacy of TBI,” says Stabenfeldt. therapeutic interventions”. “Using an established mouse model allows us to conduct biomarkers that explore the complexity and progression of progressive trauma pathology.”

Scientists can often start designing therapeutic agents or diagnostic devices based on biomarker discovery. Stabenfeldt’s team used a “bottom-up” approach to biomarker discovery.

The study’s first author Briana, a PhD student in Stabenfeldt’s lab, says the “top-down” discovery approach focuses on assessing candidate biomarkers based on their known involvement in the condition of interest” analyzes changes in tissue composition and seeks to connect those changes to the disease state. It is an unbiased but potentially risky approach. because you can identify markers that are not specific to the condition or pathology of interest.”

Next, they used a number of modern ‘bioprocessing’ tools and techniques to identify and capture the molecules, including one such ‘bait’ technique to capture the target molecules. Potentially known as phage display system, in addition to high speed DNA sequencing to identify protein targets in the genome and mass spectrometer for sequencing peptide fragments from phase visualization experiments.

Another barrier to discovery is the unique physiology of a mesh-like network designed to protect the brain from injury or harmful chemicals, known as the blood-brain barrier (BBB).

“The blood-brain barrier (BBB) ​​is the barrier that separates blood vessels and brain tissue,” explains Stabenfeldt. “In a healthy person, the BBB tightly regulates the metabolism of nutrients and waste from the blood to the brain and vice versa, essentially blocking the brain/central nervous system.”

‘However, this barrier also complicates drug delivery to the brain so that most molecules/drugs do not pass through this barrier passively; As a result, the drug delivery sector has sought to regulate both drug entry and delivery mechanisms. Similarly, for blood-based biomarkers for TBI or other neurodegenerative diseases, pathologic specificity and molecular transfer (if it originates in the brain) from brain to blood is challenging. . ”

When TBI occurs, the initial trauma can disrupt the BBB, causing a cascade of dead cells, torn, broken tissues, and debris.

Long-term damage causes inflammation and swelling, leading to an immune response kicking in, but can also lead to a decrease in the brain’s energy source, or it can block blood supply to the brain, leading to death. more neurons and permanent disability.

A key advantage of the phage display system’s engineering and experimental toolkit is that the molecules and potential biomarkers identified are small enough to pass through the tiny holes in the BBB’s mesh—thus , which opens the way for therapeutics based on these molecules.

So despite all these obstacles, the team found a way.

“Our study leverages phage sensitivity and specificity to uncover novel targeting motifs,” said Stabenfeldt. “Combination of phage and NGS [next-generation sequencing] has been used before, thus taking advantage of bioformat analysis. The unique contribution of our study is to bring all these tools together specifically for the TBI model in vivo. ”

They found a unique set of biomarkers associated only with acute or chronic phases of TBI. In the acute phase, TBI targets recognized targets that are involved mainly in metabolic and mitochondrial (organic) dysfunction, whereas the chronic TBI motif is largely associated with neurodegenerative processes.

“Our biomarker detection method is sensitive enough to detect damage in brains collected at different points in the experiments,” said study first author Briana Martinez, a recent PhD. graduate at Stabenfeldt’s lab said. “It was really interesting to see that proteins involved in neurodegenerative diseases were detected at 7 days post-injury, but not at a earlier time-point, 1 day after injury. That’s what we do. being able to observe these differences really shows the usefulness of this approach being able to explore different aspects of brain injury.”

It may also begin to explain why people who already have TBI are more susceptible to neurodegenerative diseases like Parkinson’s and Alzheimer’s later in life.

This successful discovery process will now serve as the foundation for the next generation of targeted TBI diagnosis and treatment.

Next, the team plans to work further with ASU’s clinical partners and expand their studies to begin looking for these same molecules in human samples.

Source: Eurekalert

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