My career goal is to better understand the mechanisms governing axonal degeneration following acute brain injury and how this translates to functional deficits. Lacking previous experience in utilizing methods of molecular and cellular biology, electrophysiology, diffusion tensor imaging (DTI), and developing mouse knockout models, the time and support provided by this award will be critical for me to develop these specialized skills to assess axonal degeneration as well as to create a platform for future studies to further dissect underlying pathophysiology and test treatment strategies. Traumatic brain injury (TBI) commonly results in axonal degeneration, which constitutes a critical determinant of post-traumatic functional impairment. I hypothesize that blocking axon degeneration through Sarm1 knockout (KO) represents a novel approach to therapeutic intervention in TBI, an exciting possibility that I will explore for the first time.
Specific Aim 1 : To determine the structural integrity of Sarm1-null axons after TBI. Serial histological staining of brain tissue in Sarm1+/+ and Sarm1-/- mice will be performed using a variety of histological markers for microstructural axonal integrity. Non-invasive, longitudinal assessment of axon integrity will be determined using serial in vivo DTI.
Specific Aim 2 : To determine the functional impact of Sarm1 KO after TBI. Direct assessment of axonal function in vivo will be determined by transcallosal evoked potentials. Behavioral impairment will be assessed serially using a battery of sensory-motor tests.
Specific Aim 3 : To develop model systems in which Sarm1 function can be eliminated in a cell-type specific and temporally regulated fashion to block axonal degeneration after TBI. Creating conditional Sarm1 KO mice allows testing the hypothesis that Sarm1 KO neuron-autonomously protects from axon loss after TBI in the adult brain. This proposal outlines my training plan to take advantage of coursework and a strong mentoring team (Drs. Brown, Freeman, King, Schwartz, Jones, Ayata) with broad expertise in the proposed methods (axon degeneration, mouse electrophysiology & behavior, small animal MRI, conditional KO mouse models) to fill key gaps in my previous training to advance my career goals. The expertise gained during this training will uniquely position me to test my hypothesis that Sarm1 KO mitigates traumatic axonal degeneration and improves cellular and behavioral outcomes following mouse TBI. This study has the potential to provide some of the first molecular insights into the mechanisms of axon loss during TBI. Moreover, identifying a role for Sarm1 in axon loss after TBI would indicate that anti-Sarm1 therapeutics might represent an exciting new approach to brain protection with potential application to many other types of brain injury.
Traumatic brain injury (TBI) is a leading cause of disability with an estimated 5 million Americans living with long-term disability related to TBI and associated annual direct and indirect costs in excess of $70 billion. Traumatic degeneration of axons, the functional connection between neurons in the brain, is a hallmark of TBI and key cause of post-traumatic functional deficits. This study will investigate whether blocking of the first discovered gene to drive a genetic axon death program (Sarm1) in mice reduces post-TBI axon degeneration and whether this translates to improved behavioral outcome.
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