Human genetic studies have revealed the importance of autophagy in the pathogenesis of Inflammatory Bowel Diseases (IBD). Autophagy is a cellular disposal system that directs cargoes into lysosomes, where the substrates, ranging from proteins to pathogens, are subjected to proteolytic cleavage. Several Crohn's disease (CD) susceptibility genes identified in genome wide association studies, such as ATG16L1, IRGM, and NOD2 have been implicated in the regulation of autophagy. Failure of autophagosome formation, maturation and cargo recognition have been correlated with CD-relevant phenotypes, such as impaired clearance of intracellular bacteria and prolonged pro-inflammatory responses, in mouse models as well as in patient-derived samples. These data have led to the hypothesis that small-molecule enhancers of autophagy may correct specific immune phenotypes caused by genetic variants observed in IBD patients. Our current research focuses on the investigation of the cause of Crohn's disease by identifying highly selective small-molecule probes that target autophagy through a high-throughput screen (HTS), by using the resulting lead compounds in mechanism of action (MOA) studies to identify cellular targets to further our understanding of the disease biology, and by testing the therapeutic potential of these compounds in animal models of the disease phenotype. In addition to providing insight into the cause and treatment of Crohn's disease, a collection of autophagy probes with known MOAs could drive future experiments to address the role of autophagy in neurodegeneration and cancer, where this process has been implicated yet remains poorly understood. Our efforts to develop selective, small-molecule modulators of autophagy, including synthetic and medicinal chemistry endeavors, autophagic flux assays, bacterial co-localization and clearance experiments, inflammatory cytokine measurements, and mechanism of action studies, will be highlighted.

Development of small-molecule autophagy modulators for the study of Crohn's disease

246th National Meeting (2013)

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