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E. A. Blakely, P. Y. Chang, K. A. Bjornstad, C. J. Rosen; Particle Radiation Alters Expression of Matrix Metalloproteases Resulting in ECM Remodeling in Human Lens Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4915.
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Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) have been implicated in normal and pathological lens growth, development and remodeling. Exposure to relatively low doses of particle space radiation has been correlated with an increased incidence and earlier appearance of cataracts in astronauts. The goal of our research is to understand mechanisms associated with particle radiation-induced cataractogenesis. Our approach is to screen for particle radiation-induced changes in genes that are implicated in extracellular matrix (ECM) communication. We have previously reported that selected MMPs are dramatically down-regulated shortly after a single dose of low LET proton exposure in our normal differentiating human lens cell model. We have extended our proton studies and also included work with heavier charged particle beams prevalent in space.
A cultured human lens epithelial cell model (Blakely et al, IOVS 41: 3808, 2000) was used for these studies. Lens cells were grown on matrix-coated plastic tissue culture vessels and irradiated with several high energy charged particle beams with different energy deposition profiles. These include (1) 55 MeV/u proton particle beams at the 88" cyclotron at Berkeley Lab, (2) 600 MeV/u and 1 GeV/u iron ions and (3) 1 GeV/u titanium ions at the NASA Space Radiation Lab at Brookhaven National Lab. Total RNA and protein extracts from sham-treated control and irradiated samples were harvested at different times after radiation exposure, processed and probed for the expression of genes associated with ECM proteases. Several of the genes showing differential signals were identified and further validated using quantitative PCR methods and Western analysis. Independent replicates of experiments were completed.
We have evidence for radiation-quality dependent alterations in MMP 2, 3 and 9. The regulation of TIMP1 was reduced 8 hrs after heavy ion exposure, in contrast to the early response after protons. Additional studies on MMP expression as a function of Linear Energy Transfer (LET) and lower doses in a time course after radiation are underway.
Our data indicate that radiation-quality-dependent differences in the damage produced by particle radiations can lead to differences in the expression of radiation stress responses. Such responses are sensitive to the differentiation status of the human lens cells and may impact selective ECM remodeling leading to lens pathology.
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