Project Summary/Abstract
Global incidence of Traumatic Brain Injury (TBI) is on the rise, particularly among athletes, military personnel,
and elderly citizens1. TBI represents a spectrum of mild to severe injuries that share many long-term pathologies
and clinical symptoms such as Tau and TDP43 pathology, axonal injury, neuronal death, and increased risk of
depression and neurodegenerative diseases2-6. Although end-stage pathologies are well characterized from
post-mortem samples, the molecular mechanisms contributing to injury remain poorly understood in part due to
the difficulty of studying live brains in human patients and the variable biophysical processes that occur between
patients. As a result, available treatment options remain limited and are largely ineffective61. Previous studies of
TBI conducted in animal models present with edema, inflammation, and blood-brain barrier disruption following
an induced trauma6,7. Although important to the pathophysiology of TBI, this complex cascade of events
complicates our ability to accurately understand cell autonomous injury mechanisms. Therefore, a reductionist
system to study the response of distinct cell types to TBI would be beneficial for identifying and targeting changes
that occur post-injury. To this end, we will utilize a 3-D cortical organoid culture system grown from human
induced Pluripotent Stem Cells (iPSCs) to elucidate cell autonomous mechanisms of injury and degeneration
caused by TBI8. We have developed a unique system of focused ultrasonic injury to mimic TBI in vitro which
recapitulates key pathologic and transcriptional features of in vivo models. This allows for detailed study of both
acute and chronic changes following an induced trauma, and provides a platform to integrate environmental and
genetic contributions to injury while preserving human-specific biology. Using this system, we will combine bulk
RNA-seq transcriptomic analysis with biochemical and immunoassays to uncover novel cell-type specific injury
mechanisms. Using iPSC lines from patients with neurodegenerative diseases, we will test how TBI modulates
genetically-induced disease mechanisms. Finally, we will test a mouse model of cortical controlled impact (CCI)
to validate our findings in vivo. This proposal will greatly enhance our understanding of specific injury
mechanisms in discrete cell types and may help to identify novel neuroprotective therapeutic targets.
