Autophagy represents a complex pathway of cellular homeostasis that functions in cytoprotection, but if dysregulated can cause cell death; a complete knowledge of regulation is critical for the potential modulation of this process for therapeutic purposes, and to increase our basic understanding of membrane dynamics and organelle biogenesis. Autophagy occurs in all eukaryotes and the protein components of the autophagic machinery are conserved from yeast to mammals. The hallmark of this process is the formation of double- membrane cytosolic vesicles, autophagosomes that sequester cytoplasmic components. After completion, the autophagosomes fuse with the lysosome/vacuole to release the inner vesicle that is broken down, allowing access to the cargo. Autophagy plays a role in various developmental processes and is associated with a range of pathophysiological conditions. The long-term goal of this proposal is to understand the mechanism and regulation of autophagy and how this translates into autophagosome formation. The molecular field of autophagy is slightly over fifteen years old, which is startling for a pathway with connections to such a wide range of physiological processes. In a practical sense, this also means there are many questions remaining to be answered. For example, we want to (1) determine how environmental signals are transduced into an autophagic response, defining the kinases, phosphatases and transcription factors that control autophagy; (2) identify the origin of the sequestering compartment and determine how membrane from a variety of organelles can be commandeered to provide the material needed for autophagosome formation; and (3) understand what regulatory controls determine the switch between specific and non-specific types of autophagy, and the method of achieving cargo specificity. We are using yeast to investigate the molecular mechanism of autophagy; this is the best system for a molecular genetics and biochemical analysis of this complex process. Because of the high degree of conservation, however, the information we learn from yeast will be applicable to higher eukaryotes. At present, almost forty autophagy-related (Atg) proteins have been identified, but their functions and the regulatory processes that control them are largely undefined. The experiments described in this proposal are significant because they will elucidate important links between upstream regulatory components and the machinery that carries out autophagy, providing the next step in a comprehensive analysis that links the signal transduction elements to the functional apparatus, advancing our knowledge of basic cell biology, and identifying targets for ultimate therapeutic intervention. The proposed research is innovative, because it is providing new, and in some cases paradigm-shifting, information about the regulatory and functional components of autophagy.
Autophagy plays a role in normal developmental processes including fetal development and innate immunity, and its dysfunction has been implicated in a wide range of human diseases including cancer, some types of neurodegeneration, bacterial and viral infections, gastrointestinal disorders, diabetes and heart disease. It may be possible to modulate autophagy for therapeutic purposes, turning it on and off at precise times, and in specific tissues, to prevent or ameliorate the onset of diseases or their symptoms. To use autophagy in this manner, however, will require a complete understanding of its mechanism and regulation.
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