The long-term goals of this study are to understand the molecular basis of autophagy and its role in erythropoiesis. Autophagy is a catabolic process in which cytosolic components, including organelles, are sequestered in double-membrane autophagosomes and delivered to the lysosome for degradation and recycling of essential components (amino acids, nucleotides, etc). Autophagy plays important roles in regulating a range of cellular processes, from organelle turnover to the mobilization of amino acids upon starvation, and defects in autophagy have been associated with a number of human diseases including cancer. The genes involved in autophagy (Atg genes) have been best characterized in yeast and although the many of the mammalian homologues have been identified have not been characterized in terms of their roles in autophagy. Among these genes are Ulk1 and Ulk2, the mammalian homologues of Atg1. Atg1 is critical for the induction of autophagy in yeast. I propose to examine the role of these Atg1 homologues in autophagy and mitochondrial autophagy will be examined using a system that has recently been developed in our laboratory. In addition, I will use the knowledge and reagents gained from these initial studies will be used to examine the hypothesis that autophagy contributes to the degradation of organelles that is a critical step in reticulocyte maturation. Defects in the terminal stage of erythroid maturation may result in anemia and have been observed in patients with myelodysplastic syndrome. The experiments outlined in this proposal will be conducted under the mentorship of Dr. Craig Thompson. Dr. Thompson is the Chairman of Cancer Biology at the University of Pennsylvania and has an extensive track record in mentoring clinical scientists along the path to highly production research careers. This career development program will complement my clinical training as a hematopathologist and will provide the foundation for launching an independent academic career studying normal erythroid development and its relationship to hematological disorders, including myelodysplastic syndromes and acute leukemias.
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