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The general public is at risk of ionising-radiation exposure. The development of high-throughput methods to triage exposures is warranted. Current biodosimetry techniques are low-throughput and encumbered by time and technical expertise. Although there has been an emergence of gene-profiling tools for the purpose of photon biodosimetry, similar capacities do not exist for alpha-particle radiation. Herein is the first genomic study useful for alpha-particle radiation biodosimetric triage. This work has identified robust alpha-particle induced gene-based biomarkers in isolated, ex-vivo irradiated leukocytes from multiple donors. It was found that alpha-particle and photon radiation elicited similar transcriptional responses, which could potentially be distinguished by aggregate-signature analysis. Although no distinct genes were sole indicators of exposure type, clustering algorithms and principal component analysis were able to demarcate radiation type with some success. By comparing the biological effects elicited by photon and alpha-particle radiation, significant contributions have been made to the field of radiation biodosimetry.

The general public is at risk of ionising-radiation exposure. The development of high-throughput methods to triage exposures is warranted. Current biodosimetry techniques are low-throughput and encumbered by time and technical expertise. Although there has been an emergence of gene-profiling tools for the purpose of photon biodosimetry, similar capacities do not exist for alpha-particle radiation. Herein is the first genomic study useful for alpha-particle radiation biodosimetric triage. This work has identified robust alpha-particle induced gene-based biomarkers in isolated, ex-vivo irradiated leukocytes from multiple donors. It was found that alpha-particle and photon radiation elicited similar transcriptional responses, which could potentially be distinguished by aggregate-signature analysis. Although no distinct genes were sole indicators of exposure type, clustering algorithms and principal component analysis were able to demarcate radiation type with some success. By comparing the biological effects elicited by photon and alpha-particle radiation, significant contributions have been made to the field of radiation biodosimetry.

<p>Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. Previous studies have indicated that many of these changes are dependent on the activity of transcription factors belonging to the AP-1, STAT and Ets families. This study took advantage of transformation-deficient and temperature sensitive mutants of the Rous sarcoma virus to characterize transformation-induced patterns of gene expression of two primary cell types, chicken embryo fibroblasts (CEF) and chicken neuroretina (CNR). In these cells, v-Src alters the expression of up to 6% of the protein coding genes. Comparison of this program with independent breast carcinoma data sets identified a group of 42 v-Src inducible genes associated with reduced disease-free survival. Pathway and ontological analyses of the genes differentially regulated by transformation in CEF and CNR indicated a generalized program of de-differentiation induced by Src.</p> <p>To investigate the role of AP-1 inSrc-mediated transformation, a gene profiling study was conducted to characterize the transcriptomes of v-Src-transformed CEF expressing the <em>Jun</em> dominant-negative allele or the <em>JunD</em> short-hairpin RNA (shRNA). Microarray data analysis indicated a cluster of 18 co-regulated probe-sets activated in v-Src-transformed CEF with repressed AP-1 activity but not activated in normal CEF or CEF transformed only by v-Src. One gene, <em>death-associated protein kinase 1</em> (<em>DAPK1</em>), is a C/EBPβ-regulated mediator of apoptosis in IFN-γ-induced cell death. Inhibition of DAPK1 abrogated cell-death in v-Src-transformed CEF expressing the JunD shRNA and expression of DAPK1 was dependent on C/EBPβ but antagonized by AP-1. Chromatin immunoprecipitation indicated that C/EBPβ, but not JunD, is recruited to the DAPK1 promoter. In conclusion, JunD promotes survival by indirectly antagonizing C/EBPβ-dependent expression of DAPK1.</p> / Doctor of Philosophy (PhD)

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