Using ASMase knockout mice to model human diseases.

Acid sphingomyelinase (ASMase) is a key initiator of sphingomyelin/ceramide signal transduction activated by many stress stimuli. Over the past two decades, much progress has been made in defining the clinical relevance of sphingomyelin/ceramide signaling in numerous diseases using ASMase knockout mice. Organs that operate this pathway are numerous and the disease states regulated are diverse, with ceramide generation governing injury in tumor, gut, ovary, brain, lung, heart, liver, and during infection. This chapter emphasizes evolutionary conservation of sphingolipid stress signaling and mammalian adaptations that permit transduction of organotypic responses. Recognition that the sphingomyelin/ceramide transducer calibrates extent of tissue injury, ultimately acting as a molecular switch that determines organ fate, is driving development of new pharmacologic concepts and tools to intervene therapeutically.