Publication Date
2011-08-29
Availability
Embargoed
Embargo Period
2013-08-29
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PHD)
Department
Neuroscience (Medicine)
Date of Defense
2011-08-05
First Committee Member
John L. Bixby
Second Committee Member
John R. Bethea
Third Committee Member
Vance P. Lemmon
Fourth Committee Member
Helen M. Bramlett
Fifth Committee Member
R. Grace Zhai
Sixth Committee Member
McLean Bolton
Abstract
Trauma to the central nervous system (CNS) results in an irreversible disruption of axon tracts, often leading to lifelong functional deficits. Despite a large body of research into the mechanisms that underlie the lack of axonal regeneration after CNS injury, there are currently no effective treatments. One major obstacle involves the presence at injury sites of CNS growth-inhibitory molecules, such as myelin proteins and astrocyte-derived chondroitin sulfate proteoglycans (CSPGs), which act as environmental barriers to axonal regeneration. Our lab recently described the identification and characterization of a novel compound, F05, which promotes growth on inhibitory substrates in vitro. I show that F05 improves regeneration in vivo after acute sensory axon transection as well as after optic nerve crush injury. F05 does not target known signaling molecules involved in CSPG or myelin mediated inhibition but does affect growth cone microtubule dynamics, suggesting a potentially novel mechanism of growth promotion. Using a protein microarray, I show that apoptotic signaling pathways may underlie glial-derived inhibition and its relief by F05. In addition, I employed a comparative gene microarray to show that F05 induces similar changes in gene expression as antipsychotics of the piperazine phenothiazine structural class (PhAPs). Indeed, PhAPs share F05’s ability to overcome glial-derived inhibition of cultured CNS neurons and do so through a mechanism dependent on antagonism of calmodulin. These studies have led to the identification of potentially novel clinical treatments for CNS injury as well as a better understanding of environmentally derived growth-inhibitory signaling mechanisms.
Keywords
regeneration; myelin debris; chondroitin sulfate proteoglycan; antipsychotics; high content screening; CNS injury
Recommended Citation
Johnstone, Andrea, "Overcoming Glial-Derived Inhibition of Regeneration in CNS Neurons: From Novel Compounds to Novel Uses for FDA-Approved Compounds" (2011). Open Access Dissertations. 631.
https://scholarlyrepository.miami.edu/oa_dissertations/631