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Effect of Sidestream Tobacco Smoke on Parkin Null Mice

Institution: University of California, Los Angeles
Investigator(s): Owen Kelly, Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15FT-0068 Award: $48,256
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Parkinson disease is a brain disorder. It occurs when certain brain cells, that produce chemicals to allow movement and coordination, die or become impaired. When approximately 80% of the cells are damaged, the symptoms of Parkinson disease (PD) appear. 60,000 new cases are diagnosed each year, joining the 1.5 million Americans who currently have Parkinson disease. Recently, scientific evidence has found that PD patients are less prone to developing cancer and especially smoking related cancers.

Secondhand smoke can cause damage to DNA, or cause oxidative stress in cells, resulting in many diseases such as cancer and heart disease. Secondhand smoke, a known carcinogen that humans are exposed to is difficult to reproduce in a laboratory setting, so often side stream tobacco smoke (SSTS) is used, which makes up about 85% of secondhand smoke.

To facilitate the response of animals to SSTS exposure, I am proposing to use mice which have a mutated gene. The same mutated gene that causes PD in humans. To study the effects of SSTS on mice, I will look at the frequency of DNA deletions that occur on a specific piece of DNA. The deletion of DNA is an indication of genetic instability and can cause genetic mutations or even damage the DNA. Damaged or altered DNA is often the first step in how cancer starts. Since being able to see where DNA may have been deleted in a sequence of DNA is difficult, I will be using mice in which the occurrence of a DNA can be visually quantified. The assay can be used to score the frequency of DNA deletions in a specific sequence of DNA.

A valuable analysis to assess a cause and effect relationship is to use increasing amounts of a chemical, drug or toxin to induce an increasing effect, which is called a dose-response curve. In this research project, I am proposing to find a dose-response relationship between SSTS concentration and the frequency of deletions. Because I will also be using mice which mimic PD, the results of this study will also give insight into mechanisms of cancer predisposition. For example, if the mutant PD mice show a decrease in DNA deletions compared to normal mice, it can be said that humans in the general population with this mutation, may also be less susceptible to cancer.

Results from this study will also tell us if the anti-oxidant system is damaged by the mutation and also by SSTS. Finally, if the mice used in this study show a dose-response association to SSTS, they may be useful as models for further cancer studies and therapies.