Member, Biochemistry, Biophysics & Structural Biology GPB Home Area, I3T Theme, JCCC Signal Transduction and Therapeutics Program Area, Molecular Pharmacology GPB Home Area, Molecular, Cellular & Integrative Physiology GPB Home Area
1. Longevity molecules that counteract aging and extend lifespan have long been a dream of humanity. Compared to ad libitum feeding, dietary restriction (DR) consistently extends lifespan and prevents age-related diseases. We discovered that a common metabolite, alpha-ketoglutarate (a-KG), acts as a direct molecular connection between dietary restriction and major aging regulatory proteins (Chin et al. 2014). Endogenous molecules such as a-KG that increase longevity suggest that an internal “fountain of youth” may exist that is accessible to interventions. Future research in this area offers enormous hopes and possibilities for better understanding of the molecular mechanisms of aging regulation, and for the prevention and treatment of age-related diseases, including major common killers such as cancer, heart disease, diabetes, and neurodegenerative diseases. 2. A second major area of interest in the lab is in technology and method development. Development of effective and safe therapies is the holy grail of medicine. For small-molecule drugs, a key challenge remains the identification of the molecular targets underlying drug therapeutic effects and/or adverse side effects. We have developed a simple, universally applicable target identification approach that analyzes direct drug binding to its target protein but does not require modification or immobilization of the small molecule (Lomenick et al. 2009). In this method, termed DARTS (drug affinity responsive target stability), small-molecule binding results in a pronounced and specific protection of its target protein from protease digestion. This specificity can be exploited to identify unknown binding targets of a small molecule with any cell lysate or protein mixture.