Axonal damage is a hallmark of diffuse brain injuries, and is considered by many as a nearly universal consequence of traumatic brain injury. Recent evidence shows that unmyelinated axons are particularly vulnerable to damage in DAI. In this project, we study the mciromechanical aspects of axonal injury to unmyelinated axons. Our long term objective to study when sodium channel proteolysis occurs in axons after mild TBI, determine the mechanism(s) that regulate this channel proteolysis, and to evaluate the effectivenes of different biomarkers to evaluate this form of axonal damage.
Our specific aims are to:
Aim 1 : To measure the strain rate sensitive threshold for sodium channel mechanoactivation following axonal stretch injury in vitro, determining the pathway(s) that contribute to both immediate and sustained stretch-induced increases in axoplasmic calcium, Aim 2: To determine the thresholds and timecourse of sodium channel proteolysis after axonal stretch, assess if this proteolysis is mediated by calpain activation and linked to a specific stretch-induced calcium pathway, and evaluate if the proteolysis can be reduced using delayed treatments.
Aim 3 : To determine the threshold and time course of a delayed increase in membrane permeability after axonal stretch injury, examine if this permeability changes is responsive to delayed treatments, and to test if this permeability change leads to a detectable release of 'biomarkers'for detecting axonal injury in vitro. Our overall hypotheses are that (a) sodium channel mechanoactivation occurs during mild stretch injury to unmyelinated axons, (b) sodium channel proteolysis is calpain mediated, (c) the primary pathway(s) for sustained calcium elevation in axons after stretch is a critical target in controlling sodium channel proteolysis after axonal injury. Relevance: One common type of injury in head injured patients is the swelling and disconnection of axons throughout many brain regions. We will study how this injury occurs, evaluate if we can treat this injury, and will assess if there specific biomarkers that can serve as prognostic indicators of axonal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS056202-05
Application #
8377472
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$211,679
Indirect Cost
$47,634
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Siman, Robert; Shahim, Pashtun; Tegner, Yelverton et al. (2015) Serum SNTF Increases in Concussed Professional Ice Hockey Players and Relates to the Severity of Postconcussion Symptoms. J Neurotrauma 32:1294-300

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