Atg1 homologues in autophagy, mitochondrial degradation and erythroid maturation

描述(由申请人提供)： 这项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，包括细胞器在内的胞液成分被隔离在双膜自噬小体中，并被运送到溶酶体中，以降解和循环必要的成分(氨基酸、核苷酸等)。自噬在调节一系列细胞过程中起着重要作用，从细胞器周转到饥饿时氨基酸的动员，自噬缺陷与包括癌症在内的许多人类疾病有关。参与自噬的基因(ATG基因)已经在酵母中得到了最好的表征，尽管许多哺乳动物的同源物已经被鉴定，但它们在自噬中的作用还没有被表征。这些基因包括与Atg1在哺乳动物中的同源物ulk1和ulk2。ATG1在酵母中诱导自噬过程中起关键作用。我建议研究这些Atg1同源物在自噬中的作用，线粒体自噬将使用我们实验室最近开发的系统进行检测。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退化的假设，这是网织红细胞成熟的关键步骤。红系成熟末期缺陷可能导致贫血，在骨髓增生异常综合征患者中也观察到了这种情况。这项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，在指导临床科学家迈向高产出的研究生涯方面有着广泛的记录。这一职业发展计划将补充我作为血液病理学家的临床培训，并将为我开始独立的学术生涯奠定基础，研究正常的红系发育及其与血液疾病的关系，包括骨髓增生异常综合征和急性白血病。(摘要结束)

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)