Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Molecular and Cellular Biochemistry

First Advisor

Dr. Douglas A. Andres

Abstract

Traumatic brain injury (TBI) is a progressive disorder, in which the primary injury results in the initiation of a complex cascade of secondary biochemical and metabolic changes resulting in lasting neurological dysfunction and cognitive impairment. The heterogeneous nature of the disease has complicated the development of pharmacological agents to improve the outcomes of TBI; to date, no therapeutic treatment has been shown to be effective in clinical trials. Treatments targeting multiple secondary outcomes (cell death, axonal degeneration, and inflammation) may provide enhanced therapeutic efficacy following TBI.

Small Ras family GTP-binding proteins govern diverse cellular processes by directing the relay of extracellular stimuli to the activation of select intracellular signaling pathways. Rin (RIT2) is a member of the Rit subfamily of Ras-related family of GTPases, and is expressed solely within neurons of the CNS. Early cell culture models demonstrated that Rin signaled upstream of the stress-activated protein kinase, p38, and lacked the transformative abilities displayed by other members of the Ras family, suggesting functions for Rin other than cell growth and proliferation.

To begin to define the physiological function of Rin, we generated a RIT2 knockout mouse and examined the impact of Rin loss in the CNS following brain trauma. Our data demonstrates that Rin deficiency is neuroprotective following a controlled cortical impact (CCI) injury, reducing both acute hippocampal neurodegeneration and promoting sustained neuronal survival, without affecting post-CCI neurogenesis. Hippocampal neuroprotection achieved by Rin loss was accompanied by improved cognitive function in injured mice. Furthermore, we demonstrated that Rin loss led to blunting of axonal degeneration and microglial activation in the optic nerve following optic nerve stretch injury. The molecular interaction between Rin and dual leucine zipper kinase suggested a potential role for Rin in the regulation of a novel stress MAPK-dependent neuronal death cascade. Lastly, we demonstrated through diffuse closed head injury, that Rin loss mitigates cytokine release as a result of injury without altering glial activation.

Together, these studies establish Rin as a novel regulator of neuronal cell death, cognitive decline, axonal degeneration, and cytokine production following traumatic brain injury.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.429

Available for download on Thursday, May 10, 2018

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