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An RNA biomarker for tobacco smoke toxicity

Institution: University of California, Davis
Investigator(s): Richard Kimura,
Award Cycle: 1999 (Cycle 8) Grant #: 8DT-0174 Award: $51,751
Subject Area: General Biomedical Science
Award Type: Dissertation Awards

Initial Award Abstract
Health risks associated with exposure to tobacco smoke, such as heart disease and emphysema, ultimately result from the cellular damage caused by the toxic compounds present in large quantities in the smoke. Tobacco smoke is known to contain over 5000 chemicals (10), most of which are listed as poisons and are known to promote diseases. Situations that are damaging to the cell induce the activation of a defense system called the "cell stress response" which prevents or repairs cellular damage (1,8,9,17). Previous investigations have shown that tobacco smoke rapidly induces this defense (8,9,17). Activation of the cell stress response would be one of the first signs of cellular pathology that precedes any irreversible cellular damage or clinical symptoms attributed to the use of tobacco products.

In recent years, we have reported that cell stress dramatically increases the cellular production of a specialized class of biologically active molecules, called SINE RNA (5,6,7), which are involved in the regulation of protein synthesis (4). In stressed cells, the level of SINE RNA can increase in excess of 300 times its normal level (5,7). This rapid and vigorous response is an extremely sensitive indicator of cell stress and may potentially be used as a biomarker (diagnostic tool) to determine the threshold at which exposure to tobacco smoke causes harm to tissues. We propose to test this hypothesis by determining the sensitivity of the SINE RNA cellular defense response to tobacco smoke. This research focuses on the development of a highly sensitive and powerful biomarker (diagnostic tool) to assess the health risks of using tobacco products.

Final Report
We have recently documented a conserved and novel stress response in animals as diverse as humans and insects. Short Interspersed Repetitive Element (SINE) RNAs increase as a result of cellular insults. Silkworm Bml SINE RNAs are induced by a variety of stress treatments including aqueous tobacco smoke and one of its constituents, catechol. We further determined that Bml SINE RNAs are induced upon exposure to heat shock, heavy metals, cycloheximide and virus infection making the transient increase observed in silkworm larvae a general stress response. In this same survey, we also reported a concomitant HSP 70 mRNA response to many of the diverse stress treatments studied. Since Bml SINEs are present in approximately thirty thousand copies, and the transcripts are directed by RNA poi III, they represent an unusual class of stress genes. Due to the sensitivity of this response to many stress treatments, SINEs maybe developed as a versatile biomarker. However, tobacco products severely injure silkworm larvae presumably due to the nicotine. At the dose required for a SINE RNA response, these larvae are very close to death. Immediately upon injection, the larvae vomit a significant portion (c.c. 50% of more) of their body weight. The increase in SINE RNAs may be a secondary response to the initial effects of the acute toxicity of aqueous cigarette tar injection. To complete my study, I tested whether tobacco products induce SINE RNAs in human „ells. Unfortunately, Alu (the` human SINE) RNAs are not induced by aqueous cigarette tar in Hela cells

Stress induction of Bm1 RNA in silkworm larvae: SINEs an unusual class of stress genes.
Periodical: Cell Stress and Chaperones Index Medicus:
Authors: Kimura, R.H., Choudary, P.V., Stone, K.K., Schmid, C.W. ART
Yr: 2001 Vol: 6 Nbr: Abs: Pg: 263-272