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The focus of my research is how autophagy is regulated in multicellular organisms. Autophagy is the major cellular pathway for degrading long-lived proteins and cytoplasmic organelles and has been implicated in processes like cancer and aging. For many decades, autophagy had only been described as a phenomenon triggered by a number of stimuli, including nutrient starvation, hypoxia, and intracellular stress. Recently, the identification of a set of evolutionarily conserved genes essential for autophagy has opened new frontiers for understanding the role of autophagy in diverse biological processes.
We use the nematode (roundworm) Caenorhabditis elegans as a model system to study autophagy and its role in development because of C. elegans ease of cultivation, genetic analysis and well characterized development. Analysis of the C. elegans genome database revealed a group of conserved autophagy genes. We began our characterization of these genes by studying bec-1 in C. elegans. Its human homolog, beclin 1 had been identified as the first autophagy gene in humans and shown to be monoallelically deleted in up to 75% of various human cancers. Therefore, any insights on the function of bec-1 and autophagy in C. elegans will likely shed light on the role of autophagy in tumorigenesis in humans.
Lack of nutrients and other adverse stimuli cause C. elegans to enter an alternative yet reversible developental stage called dauer. Recently, we have shown that genes required for autophagy in C. elegans, including bec-1, are also required for the morphologic changes that occur during dauer formation. We were able to show in vivo, that dauer formation is associated with an increase in autophagy. We also showed that bec-1 is required for longevity of C. elegans mutants in the insulin-like pathway, suggesting that autophagy is essential not only in stress responses, but also in the control of cellular processes that regulate longevity during non-stressed conditions. This illustrates the complexity of the regulation of autophagy in multicellular organisms.
We plan to study the role of autophagy in C. elegans development by using forward genetics. The C. elegans model system provides an excellent tool for performing functional screens to identify new evolutionarily conserved genes that regulate bec-1-mediated autophagy. These newly identified players in the regulation of autophagy may include novel proteins that complex with BEC-1. Since autophagy has been linked to tumor suppression, any bec-1 interacting gene may identify a new candidate gene involved in cancer biology. Molecular characterization of these genes will lead to a greater understanding of bec-1 function in development and disease.
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