Why This Project:

It is known that changes in gene expression alter biological effects of. It is necessary to identify the specific genes that demonstrate altered expression after exposure to low doses of ionizing radiation and to determine pathways involved in DNA damage recognition, signaling, and repair that are associated with radiation induced adaptive and bystander effects.

Project Goals:

1. Identification of genes whose transcription is regulated in response to low levels of ionizing radiation.
2. Identification of the genes and communication pathways that control these responses to low dose radiation.
3. Identification of the cellular and molecular targets that influence adaptive response and bystander effects in response to radiation.

Research Approach:

We will use microarray technology to identify genes whose transcription is regulated by low levels of ionizing radiation. This will provide us with a molecular basis for understanding which genes are effected by low dose radiation exposure. We will approach this problem by comparing gene expression patterns induced by low vs high doses of radiation, and by identifying genes which are specific to particular radiation-modulated DNA damage signaling pathways. We will use transgenic mouse cells, deficient in genes involved in specific DNA repair pathways, to understand the mechanisms involved in radiation- induced adaptive responses. We will work to identify the cellular and molecular targets that control radiation-induced bystander effects. We hypothesize that reactive oxygen species are involved in the bystander effects and that they directly target DNA.

Comparisons of gene expression patterns of all genes in humans and mice will help identify potential proteins induced by low-dose radiation or reactive oxygen species and help define their role in mediating bystander effects. To do this our laboratory has recently acquired and purified over 60,000 cDNA clones from humans and mice. We are currently in the process of completing two studies where cells (fibroblasts) from primary mouse embryos and human skin are used to identify all the genes that have altered radiation related changes in expression. Time and dose responses in human skin cells are under investigation using a cDNA microarray which contains 8,000 known human sequences, including over 100 radiation-responsive genes.

Expected Outcomes:

Provide an increased understanding of the pathways involved in DNA repair and will:

1. Help define the role that these genes play in bystander effects and adaptive responses.
2. Help define radiation risk.