The broad focus of our research group is to define the molecular pathways that regulate aging and age-related diseases. In diverse organisms ranging from worms to mammals, the overconsumption of food dramatically decreases lifespan and calorie restriction markedly slows the rate of aging. Obesity is caused by a surfeit of nutrients, and is one of the most important pro-aging conditions identified; it shortens lifespan by significantly increasing the risk of type II diabetes, cardiovascular disease, Alzheimer’s disease, and numerous cancers. In aggregate, these diseases account for the vast majority of deaths in developed countries worldwide. What are the biological mechanisms linking nutrient status and metabolism to this plethora of diseases? To address this question, we specifically focus on mitochondria for two main reasons. First, mitochondria metabolize the vast majority of nutrients that we consume. Second, mitochondrial dysfunction has also been implicated in virtually every age-related disease. The approaches we use include a combination of genetics, molecular biology, ‘omics screens, and biochemical approaches in cells and genetically modified animals. Some examples of research projects we are currently or soon to be working on include the following: 1. The role of uncouplers of oxidative phosphorylation (e.g. uncoupling proteins, UCP1-5) in the regulation of skeletal muscle and adipose tissue metabolism, and in obesity and type II diabetes development / prevention. 2. The identification of the signals and cytoplasmic sensors that link mitochondrial metabolic changes to cell growth and tumor development. 3. The use of the C. elegans nematode as a genetic model system to understand the role of novel mitochondrial metabolic regulatory proteins in aging and metabolic physiology. 4. The development of drugs to stimulate metabolic fuel disposal as an anti-obesity and anti-aging pharmacologic strategy. 5. The mechanisms regulating the efficiency of mitochondrial oxidative phosphorylation.

IDENTIFICATION OF THE FATTY ACID-SENSITIVE INTERACTION OF MITOCHONDRIAL UNCOUPLING PROTEIN 3 AND Δ3,5Δ2,4 DIENOYL-COA ISOMERASE IN SKELETAL MUSCLE (2011) Diabetes (in revision)

Redox regulation of the orphan nuclear hormone receptor NGFI-B by thioredoxin 1 (2011) PLoS ONE (under review)

Caenorhabditis elegans UCP4 controls complex II-mediated oxidative phosphorylation through succinate transport (2011) J. Biol. Chem. (Under Review)

Mitochondrial respiratory uncoupling blocks skin carcinogenesis (2011) J. Biol. Chem. (Under Review)

Identification of a redox-modulatory interaction between uncoupling protein 3 and thioredoxin 2 in the mitochondrial intermembrane space. (2011) Antioxid Redox Signal [Epub ahead of print]

Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading. (2009) Mol Cell Biol. 17, 4798-4811.

Influence of dietary fats on Ecstasy-induced hyperthermia (2007) Br. J. Pharmacol. 151, 1103.

Roles of norepinephrine, free fatty acids, thyroid status and skeletal muscle uncoupling protein 3 expression in sympathomimetic-induced thermogenesis (2007) J. Pharmacol. Exp. Ther. 320, 274-80.

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine in an animal model (2005) Crit. Care Med. 33, 1311-6.

Pharmacology: uncoupling the agony from ecstasy. (2003) Nature 426, 403-4.

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