Atg 1homologues in autophagy, mitochondrial degradation

描述（由申请人提供）： 本研究的长期目标是了解自噬的分子基础及其在红细胞生成中的作用。自噬是一种分解代谢过程，其中细胞溶质组分（包括细胞器）被隔离在双膜自噬体中并被递送到溶酶体以降解和回收必需组分（氨基酸、核苷酸等）。自噬在调节一系列细胞过程中起重要作用，从细胞器周转到饥饿时氨基酸的动员，自噬缺陷与许多人类疾病包括癌症有关。参与自噬的基因（Atg基因）在酵母中得到了最好的表征，尽管已经鉴定了许多哺乳动物同源物，但尚未就其在自噬中的作用进行表征。这些基因中有Ulk1和Ulk2，它们是Atg1的哺乳动物同源物。Atg1是诱导酵母自噬的关键。我建议研究这些Atg1同源物在自噬和线粒体自噬中的作用，将使用我们实验室最近开发的系统进行研究。此外，我将使用从这些初步研究中获得的知识和试剂来检验自噬有助于细胞器降解的假设，这是网织红细胞成熟的关键步骤。红细胞成熟终末阶段的缺陷可能导致贫血，并已在骨髓增生异常综合征患者中观察到。本提案中概述的实验将在克雷格汤普森博士的指导下进行。汤普森博士是宾夕法尼亚大学癌症生物学的主席，在指导临床科学家沿着高生产研究职业生涯的道路上有着广泛的记录。这个职业发展计划将补充我作为血液病理学家的临床培训，并将为开展研究正常红细胞发育及其与血液疾病（包括骨髓增生异常综合征和急性白血病）的关系的独立学术生涯提供基础。(End摘要）

DESCRIPTION (provided by applicant): 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. (End of Abstract)