Publication Date

2017-11-19

Availability

Embargoed

Embargo Period

2019-11-19

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2017-09-14

First Committee Member

Vance P. Lemmon

Second Committee Member

John L. Bixby

Third Committee Member

Kevin K. Park

Fourth Committee Member

Grace Zhai

Fifth Committee Member

Roberta Brambilla

Sixth Committee Member

Isaac Skromne

Abstract

Approximately 300,000 Americans are living today with permanent disability related to traumatic spinal cord injury (SCI), with almost 12,000 new cases each year. There are no current methods to promote robust regeneration and long-term functional recovery in SCI patients. This is partially because, following SCI, axon regeneration in the CNS is poor, owing both to neuron intrinsic factors and to external inhibitory factors. One major intrinsic limitation on axon regeneration is the altered activities of regeneration-associated transcription factors (TFs) in mature neurons of the central nervous system (CNS); these factors fail to be activated post-injury. In contrast, axons in the peripheral nervous system (PNS) acquire the ability to regenerate their axons long distances following injury at least partially by upregulating and/or activating a suite of TFs. TFs that are implicated in successful PNS regeneration, such as Stat3, cJun, Smad1, and ATF3, have been shown to promote limited axon regeneration when overexpressed in the CNS. The activities of TFs can be boosted by the addition of extrinsic transcriptional activation domains such as VP16. This strategy has been used with the TFs Klf7 and CREB to improve regeneration in vivo. An additional approach is suggested by previous findings from our lab showing that overexpression of two or more TFs can significantly increase neurite outgrown in CNS neurons in vitro. However, even with current “successful” strategies, the number of axons found to regenerate past the sites of injury in vivo remains low. Moreover, functional recovery can be elusive, as even fewer axons remake connections to their original targets. Thus, I hypothesize that a combinatorial approach of transcription factors modified with activation domains is necessary to promote robust CNS regeneration and functional recovery after injury.

Keywords

axon regeneration; transcription factors; spinal cord injury; optic nerve crush; activation domains; Stat3

Available for download on Tuesday, November 19, 2019

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