A systems biology approach for identification and stepwise validation of pharmacotherapy candidates for traumatic brain injury
Abstract
Traumatic brain injury (TBI) is caused by mechanical force to the head, most often in traffic accidents, sports or falls.Annually over 50 million people worldwide suffer TBI and for over 40% it causes chronic disabilities.TBI initiates complex secondary damage, including e.g.inflammation, neurodegeneration, and oxidative stress.Despite hundreds of pre-clinical and clinical studies, there is no pharmacotherapy that could prevent disabilities post-TBI.This thesis aimed to characterise chronic transcriptomic profiles after fluid percussion injury (FPI) induced TBI in three brain areas and investigate whether DNA methylation or transcription factors regulate transcriptomics.Moreover, the aim was to identify novel pharmacotherapy candidates by using a systems biology approach and to set up a stepwise validation pipeline.Transcriptomics analysis found upregulation of immunity and inflammatory as well as downregulation of ionchannel and mitochondrial genes in the cortex and thalamus three months post-TBI.DNA methylation was not found as a main regulator of chronic transcriptomics.However, transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated chronically post-TBI and are potential regulators of transcriptomics.A systems biology approach utilizing transcriptomics and identified transcription factors indicated antidepressants, neuroleptics and anti-cancer drugs used in clinics as candidates to enhance recovery after TBI.Desmethylclomipramine, the main metabolite of…
How strong is the evidence?
Evidence Hub reads this as a thesis, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health. Reported size: 50 participants or records.
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