The major goal of this project is to understand how the NAD+-dependent deacetylase SIRT1 regulateshepatokines that are secreted by the liver and how this process slows the progression of non-alcoholic fatty liverdisease (NAFLD) and obesity. Obesity or being overweight affects approximately 70% of U.S. adults andincreases the prevalence of developing NAFLD and Type 2 diabetes. Type 2 diabetes is a life-threateningdisease characterized by peripheral insulin resistance, which dysregulates inter-tissue communication topromote hyperglycemia and dyslipidemia.

Exposure of cells to environmental agents, such as radiation, heavy metals, air pollutants andmutagenic chemicals, generates DNA double-strand breaks (DSB)s and other chromosomallesions, and can also cause replicative stress.

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting millions of Americans.Neurons have a large amount of polyunsaturated fatty acids in membrane phospholipids that are vulnerable toattack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains andis believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid solubleantioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remainsunproven.

Medications to help treat addiction exist for many major drugs of abuse, but not for psychostimulants, such asamphetamine, and its congeners. They are also lacking for increasingly used synthetic drugs designed to mimicthe actions of known psychostimulants. Both known and new psychoactive substances continue to pose a majorand increasing public health threat. To develop effective treatments, the mechanisms by which these stimulantsproduce their abuse-related effects need to be fully understood.