Characterizing the Neuroprotective Effects of Hypothermia as a Potential Therapeutic for Traumatic Brain Injuries via an Array of Polyculture 3D Brain Cell Models
Abstract
Characterizing the Neuroprotective Effects of Hypothermia as a Potential Therapeutic for Traumatic Brain Injuries via an Array of Polyculture 3D Brain Cell ModelsTraumatic brain injury (TBI) is one of the world~s major causes of death and disability, and is a direct result of blast impact or rapid acceleration and deceleration of the brain [1-4]. At a cellular level TBI is generally classified morphologically as diffuse axonal injury (DAI) or axonal swelling, the precursor to neuronal degeneration and neuronal apoptosis [5-7]. Because the injury progression is still not well understood at the cellular scale, there exist only limited therapies fordealing with brain injuries, one of which is the administration of temporary hypothermia [8, 9].Hypothermic treatment is of great interest as a clinical therapeutic due to its simplicity in administering. However, its effectiveness in reducing cellular damage due to TBI is still being investigated even after several decades [10-12]. Part of the challenge has been in understanding the precise mechanism by which hypothermia affects different cells in the brain from thevasculature endothelium down to astrocytes and neurons. Clinical applications of hypothermictreatment have seen some benefit, in particular in reducing intracranial pressure in more severebrain injuries, but have shown only limited success in stopping diffuse axonal injury in animal models [10, 11, 13, 14]. A key question on whether a particular combination of hypothermic temperature and exposure ranges will significantly improve the neuroprotective outcome still remains to be answered. Given the brain~s complexity in cell numbers and cell phenotypes in-vitromodels are ideal candidates to identify the specific mechanism by which hypothermia affects neurons. Recent completed work by our laboratory has shown that application of mild hypothermia (33~C) significantly reduced neuronal cell death lending credible support to the use of hypothermia as a neuroprotective therapeutic for treating traumatic brain injuries. Based on these prior results, we will systematically investigate the time-temperature parameter space that renders hypothermia neuroprotective against traumatic brain injuries whilesimultaneously increasing the level of sophistication of the employed 3D cell culture models towards in-vivo complexity. The goal of this 3-year proposal is to investigate whether the neuroprotective effect of hypothermia, which we demonstrated in neurons, is preserved in the presence of various types of glial cells, and whether the same beneficial hypothermic parameterspace can be realized in cultures of higher physiologically relevance and complexity. Building upon our previous 3D imaging and cell culture infrastrutrure, we will track spatial and temporal changes in neuronal, astrocyte and glial viability and morpholgy in all three dimensions, thereby determining how hypothermia affects more physiologically realistic, brain-mimickingpolycultures as a function of injury level, temperature and time.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 30, 2016
- Source ID
- N000141612869
Entities
People
- Christian Franck
Organizations
- Brown University
- Office of Naval Research
- United States Navy