Goals and Current Projects
Our multidisciplinary TBIRC team is focused on discovering the anatomical and molecular basis of the various types of TBI in order to develop diagnostic or prognostic biomarkers and novel therapies. Our approach is to develop and analyze animal models of brain injury in parallel with studies of patients with TBI. This will allow us to understand the fundamental mechanisms of TBI and later life illnesses with which it is associated.
Our goals are: a) to model the problems underlying brain trauma due to blast, concussions and axonal injuries; b) to correlate experimental findings in rodent models with observations from traumatic injury in human brains in order to better understand pathogenic mechanisms; c) to develop brain imaging approaches or chemical reactions in the cerebrospinal fluid or serum (what we call “biomarkers”) to diagnose or predict the outcome of TBI; and d) to formulate and test experimental treatment approaches involving small organic compounds, trophic factors, and stem cells. Described below are examples of three separate but linked projects that focus on these issues.
Animal models of diffuse axonal injury/multiple-system disconnection
Animal models of diffuse axonal injury/multiple-system disconnection. This project utilizes the impact acceleration model developed by Dr. Marmarou. We are using the tools of regenerative medicine to repair damaged brain circuits with neuronal and glial precursor cells. Our team has had previous successful experience with circuit regeneration in the spinal cord and anterior brain using a variety of neural stem cell preparations. Our main idea is that neural precursors prepared in such a fashion as to differentiate into neurons or oligodendrocytes hold great promise as means to regenerate injured or dead neurons and axons in key associative and cortico-subcortical circuits. Another part of this project uses genetically modified stem cells to express light-sensitive genes that turn on or turn off neuronal function. In this fashion, after we engraft the light-sensitive cells, we can study whether brain elements differentiated from grafts exert specific physiological functions in the adult nervous system.
Diffuse axonal injuries are very common, especially after motor vehicle accidents that involve angular acceleration and shearing stress/injury of axons. The signature neuropathology is axonal swellings and retraction balls, best depicted with amyloid precursor protein immunocytochemistry (top). Structural brain imaging (MRI, bottom of image) can detect multiple microhemorrhages in the form of black hemosiderin deposits (red arrows in this susceptibility weighted sequence) and diffuse or local brain atrophy.
This project is funded, in part, by the Maryland TEDCO.
Blast injury in human brain and animal models
This project utilizes brain tissues from veterans exposed to combat blast provided through a collaborative agreement with AFIP. In parallel, the project uses a shock tube model of blast injury that was developed in collaboration with Dr Ibolja Cernak when she was at the APL. The neuropathological consequences of blast injury in humans and experimental animals are characterized and compared. Emphasis is on particular types of diffuse axonal injury and chronic neuroinflammation in the form of activated microglial cells. Lessons from animal models are used to clarify mechanisms of blast injury in the human brain.
Metal Blast Injury Military blast injuries (top part of image, a real blast event recorded by a surveillance plane in the Iraq theater) are very complex and include the primary overpressure effect, effects from shrapnel hitting the head, contusions from ejection and then falling of the body and thermal and anoxic events. The resulting neuropathologies are still poorly understood. Brain MRI at the bottom (FLAIR) corresponds to one of the soldiers involved in the blast event of top panel and shows white matter disease with areas of necrosis.
This project is funded, in part, by the Department of Defense.
Other media links:
Reuters.com video – August 13, 2015
Hidden Damage Revealed in Veterans’ Brains
USA Today, 2015
Bomb-induced brain injury may be its own disease
Washington Post, 2015
Wounds of war that never heal
Hopkins News Media Release, 2014
Combat Veterans’ Brains Reveal Hidden Damage from IED Blasts
Animal models of chronic traumatic encephalopathies
This project focuses on the cellular and molecular mechanisms of injury-induced tauopathies using a repeat-concussion model. This model is based on the impact acceleration (Marmarou) apparatus that was adjusted for use in mice. Genetically modified mice are used to explore the burden of genetic and concussive contributions to traumatic encephalopathies (diathesis-stress design). Diagnostic biomarkers are being developed with Dr. Martin Pomper and his team in Radiology using tau-and-kinase-binding molecules. Experimental therapies are explored with tau compounds.
This project is funded, in part, by the Johns Hopkins Brain Sciences Institute (BSi).