1 |
Overcoming Glial-Derived Inhibition of Regeneration in CNS Neurons: From Novel Compounds to Novel Uses for FDA-Approved CompoundsJohnstone, Andrea 29 August 2011 (has links)
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.
|
2 |
Elucidating the Role of Endogenous Electric Fields in Regulating the Astrocytic Response to Injury in the Mammalian Central Nervous SystemBaer, Matthew L 01 January 2015 (has links)
Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the regenerative potential demonstrated between mammalian and non-mammalian vertebrates. For example, astrocytes in both mammalian and non- mammalian vertebrates begin migrating towards the lesion within hours and begin to proliferate after an initial delay of two days; subsequently, astrocytes in non-mammalian vertebrates support neurogenesis and assume a bipolar radial glia-like morphology that guides regenerating axons, whereas astrocytes in mammals do not demonstrate robust neurogenesis and undergo a hypertrophic response that inhibits axon sprouting. To test whether injury-induced electric fields drive the astrocytic response to injury, we exposed separate populations of purified astrocytes from the rat cortex and cerebellum to electric field intensities associated with intact and injured mammalian tissues, as well as to those electric field intensities measured in regenerating non-mammalian vertebrate tissues. Upon exposure to electric field intensities associated with uninjured tissue, astrocytes showed little change in their cellular behavior. However, cortical astrocytes responded to electric field intensities associated with injured mammalian tissues by demonstrating dramatic increases in migration and proliferation, behaviors that are associated with their formation of a glial scar in vivo; in contrast, cerebellar astrocytes, which do not organize into a demarcated glial scar, did not respond to these electric fields. At electric field intensities associated with regenerating tissues, both cerebellar and cortical astrocytes demonstrated robust and sustained responses that included morphological changes consistent with a regenerative phenotype. These results support the hypothesis that physiologic electric fields drive the astrocytic response to injury, and that elevated electric fields may induce a more regenerative response among mammalian astrocytes.
|
Page generated in 0.0181 seconds