Role of BCL-XL in cell death after spinal cord injury

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dc.contributor.advisor J .Regino Perez -Polo en_US
dc.contributor.committeeMember Olivera Nesic -Taylor en_US
dc.contributor.committeeMember Jacqueline Bresnahan en_US
dc.contributor.committeeMember Golda Leonard en_US
dc.contributor.committeeMember Giulio Taglialatela en_US
dc.creator DIANA M . CITTELLY en_US
dc.date.accessioned 2011 -12 -20T16 :05 :44Z
dc.date.accessioned 2014 -02 -19T22 :05 :49Z
dc.date.available 2009 -06 -09 en_US
dc.date.available 2011 -12 -20T16 :05 :44Z
dc.date.available 2014 -02 -19T22 :05 :49Z
dc.date.created 2006 -12 -14 en_US
dc.date.issued 2006 -12 -11 en_US
dc.identifier.other etd -12142006 -152807 en_US
dc.identifier.uri http : / /hdl .handle .net /2152 .3 /293
dc.description.abstract Long term functional impairment after rat spinal cord injury (SCI ) results from secondary apoptosis regulated in part , by SCI -induced decreases in protein levels of the anti -apoptotic protein Bcl -xL . In this dissertation , I assessed the role that Bcl -xL subcellular re -routing and post -translational phosphorylation play in SCI -induced Bcl -xL decreases , and evaluated the therapeutic potential of Bcl -xL -administration after SCI . Immunohistochemical analysis showed non -phosphorylated Bcl -xL in neurons and oligodendrocytes , but not in astrocytes and microglia . Bcl -xL levels decreased in mitochondria , endoplasmic reticulum , nuclei and cytosolic extracts during the first 24h after SCI , but with a different time course for each organelle ; suggesting an independent regulation of Bcl -xL shuttling from the cytosol to each compartment in the injured spinal cords . A membrane -bound phosphorylated form of Bcl -xL (P -ser62 -Bcl -xL ) was found in neurons in the uninjured SC . SCI did not affect P -ser62 -Bcl -xL levels in organelles ; however , P -ser62 -Bcl -xL appeared in the cytosol early after SCI , suggesting a role for phosphorylation in SCI -induced decreases of Bcl -xL levels . Vinblastine -induced apoptosis of neuronal PC12 cells , showed that cytosolic phosphorylated Bcl -xL correlated with apoptotic cell death of neurons , suggestive of Bcl -xL -phosphorylation as a pro -apoptotic event . I found that activated microglia /macrophages robustly expressed Bcl -xL , 7 days after SCI , and a fraction of this population undergoing apoptosis , expressed P -ser62 -Bcl -xL . Therefore , phosphorylation of Bcl -xL may have two opposite effects in injured spinal cords : (a ) it may decrease levels of the anti -apoptotic Bcl -xL in neurons and therefore contribute to their death and , (b ) it may regulate apoptosis in activated microglia /macrophages , thus curtailing the inflammatory cascades associated with SCI . \r \nTo counteract SCI -induced decreases in Bcl -xL and resulting apoptosis , I used a fusion protein made up of the TAT protein transduction domain and the Bcl -xL protein (Tat -Bcl -xL ) , or to its anti -apoptotic domain BH4 (Tat -BH4 ) . Intrathecal delivery of Tat -Bcl -xL , or Tat -BH4 for 24h or 7 days after SCI , resulted in a significant decrease in apoptosis at the site of injury . However , the 7 day delivery of Tat -Bcl -xL or Tat -BH4 impaired locomotor recovery beyond the drug delivery time . Here I show that the 7 day application of Tat -Bcl -xL or Tat -BH4 increased microglia /macrophage activation and /or survival associated with an increase in neuronal losses . These results suggest that the anti -apoptotic treatment may shift neuronal apoptosis to necrosis , and initiate an inflammatory response (microglial activation ) in SCI rats . As a result , Tat -Bcl -xL /Tat -BH4 -induced increases in proinflammatory reactions may amplify SCI -induced neuronal cell death and additionally impair functional recovery . Given that microglial activation and inflammation are main players in shaping pathological outcomes after SCI , these results suggest that the therapeutic potential of Tat -Bcl -xL or Tat -BH4 in injured spinal cords may be limited . Moreover , chronic treatment of SCI with Tat -Bcl -xL or other anti -apoptotic treatments targeting Bcl -xL could be detrimental . \r \n en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author . Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works . en_US
dc.subject Tat -BH4 en_US
dc.subject Tat -Bcl -xL en_US
dc.subject subcellular localization en_US
dc.subject spinal cord trauma en_US
dc.subject phosphorylation en_US
dc.subject neuronal death en_US
dc.subject microglial activation en_US
dc.subject Apoptosis en_US
dc.subject anti -apoptotic therapy en_US
dc.title Role of BCL -XL in cell death after spinal cord injury en_US
dc.type.genre dissertation en_US
dc.type.material text en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Cell Biology en_US

Citation

Role of BCL-XL in cell death after spinal cord injury. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /293 .

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