Genetic Networks Modulating Retinal Injury

Abstract

Dissertation AbstractMany advances have and are being made with the advent of modern sciences. One area that remains resistant to significant advances is the recovery of the mammalian central nervous system (CNS) after injury. Considerable efforts were placed on understanding the cellular and biochemical changes occurring after injury and during wound healing. Aside from cataloging the changes that occur, little progress is being made in understanding the molecular cascades associated with the control of the healing process. The present series of studies define the global changes that occur after injury. They also define CNS repair mechanisms by identifying genetic networks that underlie the temporal changes of retinal wound healing. Gene expression changes in the injured rat retina were analyzed with microarray technology, genetic linkage analysis of gene expression, and higher-level bioinformatic analyses. This work yielded three complementary insights. First, groups of functionally related genes underlie the early, delayed, and sustained responses of wound healing. For example, transcriptional factors such as Fos and Egr1 define the early response, whereas, glial reactive markers such as Gfap and Cd81 define the sustained response.

Genomic Loci Modulating the Retinal Transcriptome in Wound Healing

“…We used quantitative trait locus (QTL) analysis to discover the mechanisms regulating gene expression (Vazquez-Chona et al 2005; Chesler et al 2005). Expression QTL (eQTL) analysis combines transcriptome profiling with linkage analysis to reveal chromosomal loci modulating expression variability (Darvasi, 2003; Broman, 2005; Chesler et al 2005).…”

“…Expression genetics has been instrumental in identifying candidate genes underlying complex traits, including disease and behavior (Aitman et al 1999; Karp et al 2000; Berge et al 2000). We previously found that a group of genes upregulated after central nervous system (CNS) injury (retina, brain, and spinal cord) also shares eQTLs in gene networks from the mouse forebrain (Vazquez-Chona et al 2005). Our analysis relied on the BXD recombinant inbred (RI) strains derived from experimental crosses between the C57BL/6 and DBA/2J strains (Taylor et al 1999; Peirce et al 2004).…”

“…Our analysis relied on the BXD recombinant inbred (RI) strains derived from experimental crosses between the C57BL/6 and DBA/2J strains (Taylor et al 1999; Peirce et al 2004). Expression of acute phase genes in BXD RI mouse forebrains is modulated by eQTLs on chromosomes 6, 12, and 14 (Vazquez-Chona et al 2005). This finding raised the hypothesis that these eQTLs also modulate the acute phase response of the retina.…”

“…Quantitative trait loci (QTLs) for retinal acute phase genes (Vazquez-Chona et al 2005) were defined using QTL analysis of CNS gene expression (Chesler et al 2005). Candidate modulators were defined using computational analysis of gene and motif sequences.…”

Sharing and Reusing Gene Expression Profiling Data in Neuroscience

“…Meta-analyses of brain expression data sets are also rare, thus far. Vazquez-Chona et al (2005) performed a metaanalysis of published expression data sets to identify a common response to neuronal injury. This is a good example of the use of disparate published data sets to draw biological inferences, in this case that some genes are commonly upregulated in the acute response to injury in retina, brain and spinal cord.…”