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Tobacco regulation of amyloidogenic diseases

Institution: Stanford University
Investigator(s): Ronglih Liao, Ph.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28IR-0053 Award: $1,098,139
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Research Project Award

Initial Award Abstract

According to the CDC, smoking causes nearly 6 million preventable deaths per year worldwide and 480,000 deaths per year in the United States. Cigarette smoking is a major risk factor for cancer and cardiovascular diseases and leads to premature aging. Diseases where proteins aggregate into amyloid fibrils, such as Alzheimer’s disease and cardiac amyloidosis, occur with aging. In the most common form of cardiac-associated amyloidosis, known as AL amyloidosis, patients produce an antibody and a portion of that antibody, known as the light chain (LC), bundle into protein fibrils. Similar to amyloid plaques in Alzheimer’s disease, these LC amyloid plaques deposit in the heart and cause a form of cardiomyopathy. Cardiomyopathies are frequently lethal heart diseases. In AL amyloidosis, the LC proteins are toxic to the heart. Our laboratory has explored the underlying mechanisms by which these aggregated LC are toxic. However, the mechanisms causing the LC proteins to aggregate in the body remain elusive. We believe that there are underlying triggers that induce LC proteins to aggregate. We hypothesized that exposure to tobacco smoke can be a strong risk factor to develop amyloid diseases, in particular cardiomyopathy, since the heart is one of the organs most affected by smoking. We propose to investigate this matter using our proven expertise in the cardiac amyloid disease field. We previously used rodent cardiac cells and zebrafish (a fish model widely used to study the heart) to investigate the mechanisms that lead to LC protein toxicity and cardiomyopathy. This will be the first step to understand whether smoking can trigger, predispose, or exacerbate LC-induced cardiomyopathy and amyloid diseases in general. We seek to bring awareness to patients or individuals at risk. Furthermore, we will bring attention for the first time to the risks of smoking for amyloid diseases which represent a huge burden for our society. Significantly, the CDC has defined the huge economic cost of smoking and second-hand smoke exposure in young adults. With the rising rate of young adult smokers, it is inevitable that the economic burden of smoking and medical costs will remain intertwined for decades. Therefore, understanding the risk associated with toxins such as those found in tobacco smoke for amyloidosis and cardiac diseases is particularly relevant and timely.