Open Collections

A translational approach to understanding and treating autonomic dysfunction after spinal cord injury

University of British Columbia

Spinal cord injury leads to immediate and permanent motor, sensory, and autonomic dysfunction. It is becoming increasingly recognized that autonomic dysfunctions are a top priority for individuals with spinal cord injury, lead to accelerated chronic health conditions, and impair quality of life. Fundamentally, autonomic dysfunctions after spinal cord injury, and cardiovascular dysfunction in particular, are caused by disconnection of descending sympatho- excitatory axons originating in the rostral ventro-lateral medulla and projecting to sympathetic pre-ganglionic neurons in the spinal cord. In this thesis, we develop a clinically relevant rodent model to study autonomic dysfunction after spinal cord injury, investigate the impact of neuroprotective pharmacology on autonomic function, and deploy a framework built around systems genetics to better understand how to target conserved molecular responses. Additionally, we use data from a multi-centre clinical trial to test whether optimization of cardiovascular parameters can be used as an immediately implementable ‘neuroprotective’ strategy to improve neurologic outcomes. We show that autonomic dysfunction including autonomic dysreflexia and cardiac dysfunction can be modelled in the rodent, and follow a severity-dependent pattern that is directly associated with the number of descending sympatho-excitatory axons. To help preserve these axons after injury, we show that one of the most promising neuroprotective drugs (minocycline) administered one hour after injury can improve autonomic function compared to saline controls. Next, we identify an evolutionarily conserved gene subnetwork that can be leveraged to identify novel treatments and biomarkers. Finally, we show that optimizing cardiovascular parameters leads to improved neurologic outcomes in humans with acute SCI. Overall, the work presented in this thesis provides key mechanistic and translational data that 1) increases our understanding of autonomic dysfunction after spinal cord injury and 2) provides tools to discover and translate novel therapies to the clinic.

Text

2018-09-13

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/67171

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/