J.T. Shoemaker
PhD Defense
Date: Monday, April 20th, 2015
Time: 2PM
Location: Marcus Nanotechnology 1117-1118

COMMITTEE MEMBERS:
Michelle LaPlaca, Ph.D. (Advisor)
Ravi Bellamkonda, Ph. D.
Edward Botchwey, Ph.D.
Malú Tansey, Ph. D. (Emory University)
Shean Phelps, M.D., MPH, FAAFP (GTRI)

TITLE:
Development of an in vitro model of neuroinflammation for studying secondary injury mechanisms in traumatic brain injury

ABSTRACT:
Traumatic brain injury (TBI) is a major public health concern due to its incidence (1.7 million cases in the U.S. annually) and lack of treatment options. Despite the development of promising therapies using animal models, none have translated successfully into clinical trials. The difficulty stems from the complexity of the response to an injury with causes that are highly variable. Numerous biochemical processes are triggered in response to TBI. The signaling cascades associated with inflammation are integral components of the secondary injury mechanisms that result in long-term deficits post-injury. Many of these cascades are initiated through microglial activation, which can be induced through post-injury death of, or cytokine release by other cell types. These signals are propagated by the same mechanisms as well as by signaling from other microglia. Although in vivo models have the inherent advantage of using an intact animal in which the all of the systems involved in the injury response are present, they lack the controllability of cell culture models. In vitro tissue models provide a highly tunable environment in which in vivo-like phenomena can be simulated in a controlled, reproducible fashion. Further, three-dimensional (3-D) cell culture systems provide an environment in which cellular function is closer to in vivo than is observed using traditional two-dimensional culture methods. Such models are ideally suited for studying and deciphering a complex tissue response such as that observed in TBI. The objective of this research was to generate a 3-D culture system that models the secondary injury mechanisms of TBI in vitro. This goal was addressed by: 1) creating a novel 3-D multitypic neural cell culture system composed of primary neurons, astrocytes, and microglia derived from pre- and post-natal rat central neural tissue, 2) confirming the potential for inflammation in the system through chemical stimulation, and 3) devising a method of mechanical injury to elicit the inflammation response in a manner consistent with what is observed in TBI. Overall, the research presented here sheds light on the in vitro microglial response to insult using a novel culture method, the utility of which extends beyond the purpose for which it was designed.