Secretory clusterin protein is implicated in aging, obesity, heart disease and cancer. It’s level of expression has been shown to be induced by low dose ionizing radiation. Regulatory signaling transduction processes control secretory clusterin expression. Radiation exposures and the signal protein, TGF-ß1, increase the production of secretory clusterin. Radiation exposure causes stress activation of signaling pathways that regulate the clusterin cascade pathway. P53 can suppress clusterin expression. However TGF- ß1 can over–ride this suppression, and allows massive expression of secretory clusterin. Furthermore, adding secretory clusterin to the medium suppresses TGF-ß1-induced growth suppression. This research helps define the role of secretory clusterin in radiation resistance and cancer therapy.

Project Goals

Experimental Approach

1. A ‘low dose ionizing radiation indicator’ mouse has been developed that responds to low doses of radiation with a change in secretory clusterin levels. This model will help to explore the biological consequences of low dose radiation-inducible secretory clusterin expression in animals in vivo.
   
   
2. It will be determined if knocking down clusterin’s expression can enhance TGF-ß1-induced DNA synthesis inhibition and growth suppression.
   
   
3. Secretory clusterin level will be depressed using siRNA specific to full-length clusterin mRNA, to alter expression of secretory clusterin.

Expected Outcomes