Strategies to identify differentially regulated genetic programs after spinal cord injury

• Main Author: Gris, Pavel
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2007
• Subjects: Neurology; Neurosciences
• ISBN: 9780494308141; 0494308141

This dissertation studied changes in the regulation of genetic programs following spinal cord injury (SCI). The hypothesis of the study is that the analysis of the differential gene expression profiling in the injured spinal cord will lead to identification of genetic programs which, when activated or suppressed, may improve regeneration of the spinal cord and lead to functional recovery after SCI. The first chapter is a general introduction to the thesis including a discussion of SCI and genetic profiling. The demographics of SCI and the development of the lesion and glial scar are introduced. The emphasis is placed on the role of astrocytes in SCI in light of their pro- and anti-regenerative properties. The second chapter is concerned with identifying classes of genes that are responsible for the differing abilities of the adult injured and embryonic spinal cords to support regeneration. The third chapter of this dissertation details the study of the transcriptional regulation of a single gene battery identified by microarray and in silico analysis. This chapter tested the hypothesis that molecular players identified by microarray and in silico analyses are capable of regulating the expression of glial scar genes in primary astrocyte cell cultures. The fourth chapter describes the gene expression profiling study aimed at identifying the genetic programs that might account for the improved neurological recovery in spinal cord injured rats treated with an acute anti-inflammatory treatment. The fifth chapter reflects upon the relative success of using gene expression profiling techniques to identify genetic programs critical to repair after SCI. This chapter discusses the possible venues for future research. This work identified one genetic program that appears to regulate scar formation after SCI. The regulators in this genetic program are the transcription factor SOX-9 and the cytokines: TGFβ-2, PDGF, and IL-6. The effector genes are the CBG genes: XT-1, XT-II, C-4st, laminin, and fibronectin. The output of this genetic program is the glial scar that, under untreated conditions, is non-permissive to axonal regeneration. Key words. spinal cord injury, gene expression profiling, genetic program, gene battery, glial scar, astrocytes, primary cell culture.