Richard Kolesnick, MD

[Enlarge Image] Upstream Signaling by Ceramide

The Laboratory of Signal Transduction focuses on the role of sphingolipid signaling as a stress response. In this pathway, generation of the second messenger ceramide in response to diverse environmental and pharmacologic stresses (heat, ionizing radiation, ultraviolet light, chemotherapeutic agents, oxidative challenges, etc.) occurs either by degradation of sphingomyelin or by de novo synthesis. The quality and/or quantity of the ceramide response, in combination with other signals, determines whether adaptation or apoptosis ensues. This pathway is evolutionarily conserved and is obligate for the heat shock response in yeast.

Our program uses a multidisciplinary approach involving genetics, biochemistry, and cell biology to address these issues. Knockouts of relevant genes are generated in mice and concomitantly in the nematode Caenorhabditis elegans. Studies in C. elegans provide information regarding the molecular ordering of ceramide signaling during stress and development; whereas studies in mice provide information of tissue/organ distribution of ceramide effects. The goal of these studies is to determine under what conditions the ceramide signal is involved in normal physiology and in pathophysiology of disease; when and where this pathway is important pharmacologically; and the development of lipid agents to suppress or enhance signaling through this system in vivo. Evidence to date suggests that the sphingomyelin pathway is critical for ionizing radiation-induced death of oocytes and endothelium, and serves as an important co-signal for Fas-induced death of hepatocytes.