Date of Award

5-2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Anatomy

Research Advisor

Eldone E. Geisert, Ph.D.

Committee

Edward Chaum, M.D., Ph.D. Diana A. Johnson, Ph.D. Robert W. Williams, Ph.D. Peter J. McKinnon, Ph.D.

Keywords

retina, degeneration, regeneration, microarray, glia, gliosis, gene expression, gene regulation, quantitative trait locus (QTL) analysis, expression genetics, microarray

Abstract

Many 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. Second, three specific genomic loci modulate coordinated changes in gene expression in mouse brains: regulatory loci on chromosomes 6, 12, and 14. Of the three only the regulatory locus on chromosome 12 specifically modulates the expression of a group of genes involved in early wound-healing events (mainly, the regulation of transcription, differentiation, apoptosis, and proliferation). Third, candidate genes Id2 and Lpin1 are current modulators for the network controlled by the chromosome 12 locus. Higher levels of Id2 and Lpin1 correlated with higher levels of the survival gene Crygd, and with lower levels of acute phase genes Fos and Stat3, reactive gliosis genes Gfap and Cd81, and apoptotic gene Casp3. In this body of work I have moved beyond cataloging changes in the transcriptome to identifying candidate genes modulating the retinal response to injury. During this process I developed an integrated approach of gene expression profiling and higher-level bioinformatic analyses to define genetic networks. This work not only advances our understanding of the molecular networks controlling the CNS response to injury, but may also form the basis for interventions that can rescue injured neurons and re-establish lost CNS connections.

DOI

10.21007/etd.cghs.2006.0337

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